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Wood LB, Singer AC. Neurons as Immunomodulators: From Rapid Neural Activity to Prolonged Regulation of Cytokines and Microglia. Annu Rev Biomed Eng 2025; 27:55-72. [PMID: 39805040 DOI: 10.1146/annurev-bioeng-110122-120158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Regulation of the brain's neuroimmune system is central to development, normal function, and disease. Neuronal communication to microglia, the primary immune cells of the brain, is well known to involve purinergic signaling mediated via ATP secretion and the cytokine fractalkine. Recent evidence shows that neurons release multiple cytokines beyond fractalkine, yet these are less studied and poorly understood. In contrast to ATP, cytokines are a class of signaling molecule that are much larger, with longer signaling and farther diffusion. We posit that neuron-expressed cytokines are an essential mechanism of neuron-microglia communication that arises as part of both normal learning and memory and in response to tissue pathology. Thus, neurons are underappreciated immunomodulatory cells that express diverse immunomodulatory signals. While neuronally sourced cytokines have been understudied, new technical advances make this a timely topic. The goal of this review is to define what is known about the cytokines expressed from neurons, how they are regulated, and the effects of these cytokines on microglia. We delineate key knowledge gaps and needs for new tools to define and analyze neuronal roles in immunomodulation. Given that cytokines are central regulators of microglial function, a broad new body of work is required to illuminate functional links between these neuronally expressed cytokines and sustained and transient microglial function.
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Affiliation(s)
- Levi B Wood
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; ,
| | - Annabelle C Singer
- Wallace H. Coulter Department of Biomedical Engineering, George W. Woodruff School of Mechanical Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, Georgia, USA; ,
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2
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Xie Y, Zhang T, Ma C, Guan M, Li C, Wang L, Lin X, Li Y, Wang Z, Wang H, Fang P. The underlying neurobiological basis of gray matter volume alterations in schizophrenia with auditory verbal hallucinations: A meta-analytic investigation. Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111331. [PMID: 40089004 DOI: 10.1016/j.pnpbp.2025.111331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/08/2025] [Accepted: 03/09/2025] [Indexed: 03/17/2025]
Abstract
Schizophrenia patients with auditory verbal hallucinations (AVH) frequently exhibit brain structural alterations, particularly reductions in gray matter volume (GMV).Understanding the neurobiological mechanisms underlying the changes is essential for advancing treatment strategies. To address this, a meta-analysis was conducted to identify GMV changes in schizophrenia patients with AVH and their associations with gene expression and neurotransmitter receptor profiles. The results indicated significant GMV reductions in the left and the right insula, as well as the left anterior cingulate cortex. Ontology analysis of genes associated with GMV alternations revealed enrichment in biological processes related to ion transport and synaptic transmission. Hub genes from the KCN, SCN, GN, and PRK families, along with neurotransmitter receptors such as D2, VAChT, and mGluR5, showed significant correlations with GMV changes. Furthermore, multivariate linear regression analysis demonstrated that GNB2, GNB4, PRKCG, D2, and mGluR5 significantly predicted GMV alternations. These findings suggest that GMV reductions in schizophrenia with AVH are linked to disruptions in neurobiological processes involving specific genes and neurotransmitter systems, highlighting the potential targets for therapeutic intervention.
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Affiliation(s)
- Yuanjun Xie
- Medical Innovation Center, Sichuan University of Science and Engineering, Zigong, China; Military Medical Psychology School, Air Force Medical University, Xi'an, China.
| | - Tian Zhang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Chaozong Ma
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Muzhen Guan
- Deparment of Mental Health, Xi'an Medical College, Xi'an, China
| | - Chenxi Li
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Lingling Wang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Xinxin Lin
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Yijun Li
- Military Medical Psychology School, Air Force Medical University, Xi'an, China
| | - Zhongheng Wang
- Department of Psychiatry, Air Force Medical University, Xi'an, China
| | - Huaning Wang
- Department of Psychiatry, Air Force Medical University, Xi'an, China
| | - Peng Fang
- Military Medical Psychology School, Air Force Medical University, Xi'an, China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, Xi'an, China; Military Medical Innovation Center, Air Force Medical University, Xi'an, China; Shaanxi Provincial Key Laboratory of Bioelectromagnetic Detection and Intelligent Perception, Xi'an, China.
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Philibert CE, Garcia-Marcos M. Smooth operator(s): dialing up and down neurotransmitter responses by G-protein regulators. Trends Cell Biol 2025; 35:330-340. [PMID: 39054106 PMCID: PMC11757802 DOI: 10.1016/j.tcb.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/19/2024] [Accepted: 07/01/2024] [Indexed: 07/27/2024]
Abstract
G-protein-coupled receptors (GPCRs) are essential mediators of neuromodulation and prominent pharmacological targets. While activation of heterotrimeric G-proteins (Gαβɣ) by GPCRs is essential in this process, much less is known about the postreceptor mechanisms that influence G-protein activity. Neurons express G-protein regulators that shape the amplitude and kinetics of GPCR-mediated synaptic responses. Although many of these operate by directly altering how G-proteins handle guanine-nucleotides enzymatically, recent discoveries have revealed alternative mechanisms by which GPCR-stimulated G-protein responses are modulated at the synapse. In this review, we cover the molecular basis for, and consequences of, the action of two G-protein regulators that do not affect the enzymatic activity of G-proteins directly: Gα inhibitory interacting protein (GINIP), which binds active Gα subunits, and potassium channel tetramerization domain-containing 12 (KCTD12), which binds active Gβγ subunits.
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Affiliation(s)
- Clementine E Philibert
- Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
| | - Mikel Garcia-Marcos
- Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University, Boston, MA 02118, USA; Department of Biology, College of Arts and Sciences, Boston University, Boston, MA 02115, USA.
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Erboz A, Kesekler E, Gentili PL, Uversky VN, Coskuner-Weber O. Electromagnetic radiation and biophoton emission in neuronal communication and neurodegenerative diseases. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 195:87-99. [PMID: 39732343 DOI: 10.1016/j.pbiomolbio.2024.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/08/2024] [Accepted: 12/24/2024] [Indexed: 12/30/2024]
Abstract
The intersection of electromagnetic radiation and neuronal communication, focusing on the potential role of biophoton emission in brain function and neurodegenerative diseases is an emerging research area. Traditionally, it is believed that neurons encode and communicate information via electrochemical impulses, generating electromagnetic fields detectable by EEG and MEG. Recent discoveries indicate that neurons may also emit biophotons, suggesting an additional communication channel alongside the regular synaptic interactions. This dual signaling system is analyzed for its potential in synchronizing neuronal activity and improving information transfer, with implications for brain-like computing systems. The clinical relevance is explored through the lens of neurodegenerative diseases and intrinsically disordered proteins, where oxidative stress may alter biophoton emission, offering clues for pathological conditions, such as Alzheimer's and Parkinson's diseases. The potential therapeutic use of Low-Level Laser Therapy (LLLT) is also examined for its ability to modulate biophoton activity and mitigate oxidative stress, presenting new opportunities for treatment. Here, we invite further exploration into the intricate roles the electromagnetic phenomena play in brain function, potentially leading to breakthroughs in computational neuroscience and medical therapies for neurodegenerative diseases.
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Affiliation(s)
- Aysin Erboz
- Molecular Biotechnology, Turkish-German University, Sahinkaya Caddesi No. 106, Beykoz, Istanbul, 34820, Turkey
| | - Elif Kesekler
- Molecular Biotechnology, Turkish-German University, Sahinkaya Caddesi No. 106, Beykoz, Istanbul, 34820, Turkey
| | - Pier Luigi Gentili
- Department of Chemistry, Biology, and Biotechnology, Università degli Studi di Perugia, 06123, Perugia, Italy.
| | - Vladimir N Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., MDC07, Tampa, FL 33612, USA.
| | - Orkid Coskuner-Weber
- Molecular Biotechnology, Turkish-German University, Sahinkaya Caddesi No. 106, Beykoz, Istanbul, 34820, Turkey.
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Kim YJ, Park GM, Cho WK, Woo DH. L-DOPA Promotes Functional Proliferation Through GPR143, Specific L-DOPA Receptor of Astrocytes. ACS Chem Neurosci 2024; 15:4132-4142. [PMID: 39509688 DOI: 10.1021/acschemneuro.4c00311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2024] Open
Abstract
l-3,4-Dihydroxyphenylalanine (levodopa and L-DOPA in this text), alongside dopamine, boasts high biocompatibility, prompting industrial demand for its use as a coating material. Indeed, the effectiveness of L-DOPA is steadily rising as it serves as an oral therapeutic agent for neurodegenerative brain diseases, particularly Parkinson's disease (PD). However, the effects of L-DOPA on the growth and function of astrocytes, the main glial cells, and the most numerous glial cells in the brain, are unknown. Here, we investigated whether L-DOPA is possible as a coating material on cover glass and polystyrene for rat primary astrocytes. The coating state of L-DOPA on the cover glass and polystyrene was characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle (WCA). Interestingly, L-DOPA coated on the cover glass promoted the proliferation of astrocytes but not neurons. Furthermore, L-DOPA coated on the cover glass, as opposed to polystyrene, facilitated the proliferation of the astrocytes. The astrocytes grown on L-DOPA-coated cover glasses exhibited functional receptor-activated Ca2+ transients through the activation of protease-activated receptor subtype 1 (PAR-1), recognized as an astrocytic functional marker. However, cover glass coated with 0, 500, 1000, 2000, and 4000 μg/mL L-DOPA maintained astrocyte viability, while supplementation with 500 and 1000 μM L-DOPA significantly decreased astrocyte viability. This suggests that treatments with free 500 and 1000 μM L-DOPA significantly reduced the number of astrocytes. Both Pimozide, an inhibitor of G protein-coupled receptor 143 (GPR143), also known as Ocular albinism type 1 (OA1), and CCG2046, an inhibitor of regulator of G protein signaling 4 (RGS4), reduced the viability of astrocytes on cover glass coated with L-DOPA compared to astrocytes on cover glass coated with poly-d-lysine (PDL). This suggests that L-DOPA promotes astrocyte proliferation through activation of the GPR143 signaling pathway. These findings imply that L-DOPA proliferates functional astrocytes through the activation of GPR143. These results are the first report that L-DOPA coating cover glass proliferates rat primary astrocytes with the activation of GPR143. The discovery that levodopa enhances cell adhesion can significantly influence research in multiple ways. It provides insights into cell behavior, disease mechanisms, and potential therapeutic applications in tissue engineering and regenerative medicine. Additionally, it offers opportunities to explore novel approaches for improving cell-based therapies and tissue regeneration. Overall, this finding opens up new avenues for research, with broad implications across various scientific fields.
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Affiliation(s)
- Ye-Ji Kim
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Daejeon 34114, South Korea
- Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, South Korea
| | - Gyeong Min Park
- Department of Chemistry, Chungnam National University, Daejeon 34134, South Korea
| | - Woo Kyung Cho
- Department of Chemistry, Chungnam National University, Daejeon 34134, South Korea
| | - Dong Ho Woo
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Daejeon 34114, South Korea
- Human and Environmental Toxicology, University of Science and Technology, Daejeon 34113, South Korea
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Bair A, Printy N, Choi SH, Wilkinson J, O'Brien J, Myers B, Roman D, Mahfouz TM. In Silico Design of Novel RGS2-G alpha-q Interaction Inhibitors with Anticancer Activity. J Chem Inf Model 2024; 64:8052-8062. [PMID: 39401155 DOI: 10.1021/acs.jcim.4c00932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/29/2024]
Abstract
Regulators of G-protein signaling (RGS) are a family of approximately 30 proteins that bind to and deactivate the alpha subunits of G-proteins (Gα) by accelerating their GTP hydrolysis rates, which terminates G-protein coupled receptor (GPCR) signaling. Thus, RGS proteins are essential in regulating GPCR signaling, and most members are implicated as critical nodes in human diseases such as hypertension, depression, and others. Regulator of G-protein signaling 2 (RGS2), a member of the R4 family of RGS proteins, is overexpressed in many solid breast cancers, and its levels in prostate cancer significantly correlate with the metastatic stage and poor prognosis. We sought to develop RGS2 inhibitors as potential chemotherapeutic agents utilizing structure-based drug design approaches. Available structures of the RGS2-Gα complex were used to extract a pharmacophore model for searching chemical databases. Docking of identified hits to RGS2 as well as other RGS structures was used to screen the hits for potent and selective RGS2 inhibitors. Whole cell assays showed the top 10 ranking compounds, AJ-1-AJ-10, to inhibit RGS2-Gαq interactions. Differential scanning fluorimetry showed AJ-3 to bind RGS2 but not Gαq. All 10 compounds inhibited the growth of several RGS2 expressing cancers in cell culture assays. In addition, AJ-3 inhibited the migration of LNCaP prostate cancer cells in wound healing assays. This is the first group of RGS2 inhibitors identified by structure-based approaches and that show anticancer activity. These results highlight the potential RGS2 inhibitors have to be a new class of chemotherapeutic agents.
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Affiliation(s)
- Adam Bair
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810-1599, United States
| | - Natalie Printy
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810-1599, United States
| | - So Hee Choi
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810-1599, United States
| | - Joshua Wilkinson
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Joseph O'Brien
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Brian Myers
- Department of Chemistry and Biochemistry, Getty College of Arts and Sciences, Ohio Northern University, Ada, Ohio 45817, United States
| | - David Roman
- Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Tarek M Mahfouz
- Department of Pharmaceutical and Biomedical Sciences, Raabe College of Pharmacy, Ohio Northern University, Ada, Ohio 45810-1599, United States
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Pu Y, Yang J, Pan Q, Li C, Wang L, Xie X, Chen X, Xiao F, Chen G. MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway. J Biol Chem 2024; 300:107530. [PMID: 38971310 PMCID: PMC11332907 DOI: 10.1016/j.jbc.2024.107530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Revised: 06/03/2024] [Accepted: 06/16/2024] [Indexed: 07/08/2024] Open
Abstract
Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.
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Affiliation(s)
- Yalan Pu
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China; Department of Neurology, Langzhong People's Hospital, Nanchong, Sichuan, China
| | - Jie Yang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China; Affiliated Sichuan Provincial Rehabilitation Hospital of Chengdu University of TCM, Sichuan, China
| | - Qiuling Pan
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
| | - Chenlu Li
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
| | - Lu Wang
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
| | - Xiaoyong Xie
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
| | - Xue Chen
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China
| | - Fei Xiao
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
| | - Guojun Chen
- Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, Chongqing, China.
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Dalal S, Ramirez-Gomez J, Sharma B, Devara D, Kumar S. MicroRNAs and synapse turnover in Alzheimer's disease. Ageing Res Rev 2024; 99:102377. [PMID: 38871301 DOI: 10.1016/j.arr.2024.102377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/31/2024] [Accepted: 06/06/2024] [Indexed: 06/15/2024]
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-beta plaques and neurofibrillary tangles in the brain, leading to synaptic dysfunction and cognitive decline. Healthy synapses are the crucial for normal brain function, memory restoration and other neurophysiological function. Synapse loss and synaptic dysfunction are two primary events that occur during AD initiation. Synapse lifecycle and/or synapse turnover is divided into five key stages and several sub-stages such as synapse formation, synapse assembly, synapse maturation, synapse transmission and synapse termination. In normal state, the synapse turnover is regulated by various biological and molecular factors for a healthy neurotransmission. In AD, the different stages of synapse turnover are affected by AD-related toxic proteins. MicroRNAs (miRNAs) have emerged as critical regulators of gene expression and have been implicated in various neurological diseases, including AD. Deregulation of miRNAs modulate the synaptic proteins and affect the synapse turnover at different stages. In this review, we discussed the key milestones of synapse turnover and how they are affected in AD. Further, we discussed the involvement of miRNAs in synaptic turnover, focusing specifically on their role in AD pathogenesis. We also emphasized the regulatory mechanisms by which miRNAs modulate the synaptic turnover stages in AD. Current studies will help to understand the synaptic life-cycle and role of miRNAs in each stage that is deregulated in AD, further allowing for a better understanding of the pathogenesis of devastating disease.
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Affiliation(s)
- Sarthak Dalal
- Center of Emphasis in Neuroscience, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Jaime Ramirez-Gomez
- Center of Emphasis in Neuroscience, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Bhupender Sharma
- Center of Emphasis in Neuroscience, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Davin Devara
- Center of Emphasis in Neuroscience, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Subodh Kumar
- Center of Emphasis in Neuroscience, Department of Molecular and Translational Medicine, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA; L. Frederick Francis Graduate School of Biomedicael Sciences, Texas Tech University Health Sciences Center, El Paso, TX, USA.
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Gonzalez-Hernandez AJ, Munguba H, Levitz J. Emerging modes of regulation of neuromodulatory G protein-coupled receptors. Trends Neurosci 2024; 47:635-650. [PMID: 38862331 PMCID: PMC11324403 DOI: 10.1016/j.tins.2024.05.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/13/2024]
Abstract
In the nervous system, G protein-coupled receptors (GPCRs) control neuronal excitability, synaptic transmission, synaptic plasticity, and, ultimately, behavior through spatiotemporally precise initiation of a variety of signaling pathways. However, despite their critical importance, there is incomplete understanding of how these receptors are regulated to tune their signaling to specific neurophysiological contexts. A deeper mechanistic picture of neuromodulatory GPCR function is needed to fully decipher their biological roles and effectively harness them for the treatment of neurological and psychiatric disorders. In this review, we highlight recent progress in identifying novel modes of regulation of neuromodulatory GPCRs, including G protein- and receptor-targeting mechanisms, receptor-receptor crosstalk, and unique features that emerge in the context of chemical synapses. These emerging principles of neuromodulatory GPCR tuning raise critical questions to be tackled at the molecular, cellular, synaptic, and neural circuit levels in the future.
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Affiliation(s)
| | - Hermany Munguba
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA
| | - Joshua Levitz
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10065, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA.
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Maiorov SA, Laryushkin DP, Kritskaya KA, Zinchenko VP, Gaidin SG, Kosenkov AM. The Role of Ion Channels and Intracellular Signaling Cascades in the Inhibitory Action of WIN 55,212-2 upon Hyperexcitation. Brain Sci 2024; 14:668. [PMID: 39061409 PMCID: PMC11274798 DOI: 10.3390/brainsci14070668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024] Open
Abstract
Gi-coupled receptors, particularly cannabinoid receptors (CBRs), are considered perspective targets for treating brain pathologies, including epilepsy. However, the precise mechanism of the anticonvulsant effect of the CBR agonists remains unknown. We have found that WIN 55,212-2 (a CBR agonist) suppresses the synchronous oscillations of the intracellular concentration of Ca2+ ions (epileptiform activity) induced in the neurons of rat hippocampal neuron-glial cultures by bicuculline or NH4Cl. As we have demonstrated, the WIN 55,212-2 effect is mediated by CB1R receptors. The agonist suppresses Ca2+ inflow mediated by the voltage-gated calcium channels but does not alter the inflow mediated by NMDA, AMPA, and kainate receptors. We have also found that phospholipase C (PLC), protein kinase C (PKC), and G-protein-coupled inwardly rectifying K+ channels (GIRK channels) are involved in the molecular mechanism underlying the inhibitory action of CB1R activation against epileptiform activity. Thus, our results demonstrate that the antiepileptic action of CB1R agonists is mediated by different intracellular signaling cascades, including non-canonical PLC/PKC-associated pathways.
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Affiliation(s)
| | | | | | | | - Sergei G. Gaidin
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, 142290 Pushchino, Russia (A.M.K.)
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Nürnberg B, Beer-Hammer S, Reisinger E, Leiss V. Non-canonical G protein signaling. Pharmacol Ther 2024; 255:108589. [PMID: 38295906 DOI: 10.1016/j.pharmthera.2024.108589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 12/18/2023] [Accepted: 01/08/2024] [Indexed: 02/17/2024]
Abstract
The original paradigm of classical - also referred to as canonical - cellular signal transduction of heterotrimeric G proteins (G protein) is defined by a hierarchical, orthograde interaction of three players: the agonist-activated G protein-coupled receptor (GPCR), which activates the transducing G protein, that in turn regulates its intracellular effectors. This receptor-transducer-effector concept was extended by the identification of regulators and adapters such as the regulators of G protein signaling (RGS), receptor kinases like βARK, or GPCR-interacting arrestin adapters that are integrated into this canonical signaling process at different levels to enable fine-tuning. Finally, the identification of atypical signaling mechanisms of classical regulators, together with the discovery of novel modulators, added a new and fascinating dimension to the cellular G protein signal transduction. This heterogeneous group of accessory G protein modulators was coined "activators of G protein signaling" (AGS) proteins and plays distinct roles in canonical and non-canonical G protein signaling pathways. AGS proteins contribute to the control of essential cellular functions such as cell development and division, intracellular transport processes, secretion, autophagy or cell movements. As such, they are involved in numerous biological processes that are crucial for diseases, like diabetes mellitus, cancer, and stroke, which represent major health burdens. Although the identification of a large number of non-canonical G protein signaling pathways has broadened the spectrum of this cellular communication system, their underlying mechanisms, functions, and biological effects are poorly understood. In this review, we highlight and discuss atypical G protein-dependent signaling mechanisms with a focus on inhibitory G proteins (Gi) involved in canonical and non-canonical signal transduction, review recent developments and open questions, address the potential of new approaches for targeted pharmacological interventions.
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Affiliation(s)
- Bernd Nürnberg
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany.
| | - Sandra Beer-Hammer
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany
| | - Ellen Reisinger
- Gene Therapy for Hearing Impairment Group, Department of Otolaryngology - Head & Neck Surgery, University of Tübingen Medical Center, Elfriede-Aulhorn-Straße 5, D-72076 Tübingen, Germany
| | - Veronika Leiss
- Department of Pharmacology, Experimental Therapy and Toxicology, Institute of Experimental and Clinical Pharmacology and Pharmacogenomics, and ICePhA Mouse Clinic, University of Tübingen, Wilhelmstraße 56, D-72074 Tübingen, Germany
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Beckers P, Doyen PJ, Hermans E. Modulation of Type 5 Metabotropic Glutamate Receptor-Mediated Intracellular Calcium Mobilization by Regulator of G Protein Signaling 4 (RGS4) in Cultured Astrocytes. Cells 2024; 13:291. [PMID: 38391904 PMCID: PMC10886878 DOI: 10.3390/cells13040291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 01/31/2024] [Accepted: 02/02/2024] [Indexed: 02/24/2024] Open
Abstract
Acting as GTPase activating proteins promoting the silencing of activated G-proteins, regulators of G protein signaling (RGSs) are generally considered negative modulators of cell signaling. In the CNS, the expression of RGS4 is altered in diverse pathologies and its upregulation was reported in astrocytes exposed to an inflammatory environment. In a model of cultured cortical astrocytes, we herein investigate the influence of RGS4 on intracellular calcium signaling mediated by type 5 metabotropic glutamate receptor (mGluR5), which is known to support the bidirectional communication between neurons and glial cells. RGS4 activity was manipulated by exposure to the inhibitor CCG 63802 or by infecting the cells with lentiviruses designed to achieve the silencing or overexpression of RGS4. The pharmacological inhibition or silencing of RGS4 resulted in a decrease in the percentage of cells responding to the mGluR5 agonist DHPG and in the proportion of cells showing typical calcium oscillations. Conversely, RGS4-lentivirus infection increased the percentage of cells showing calcium oscillations. While the physiological implication of cytosolic calcium oscillations in astrocytes is still under investigation, the fine-tuning of calcium signaling likely determines the coding of diverse biological events. Indirect signaling modulators such as RGS4 inhibitors, used in combination with receptor ligands, could pave the way for new therapeutic approaches for diverse neurological disorders with improved efficacy and selectivity.
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Affiliation(s)
| | | | - Emmanuel Hermans
- Institute of Neuroscience, Université Catholique de Louvain, 1200 Brussels, Belgium; (P.B.); (P.J.D.)
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13
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Luebbers A, Gonzalez-Hernandez AJ, Zhou M, Eyles SJ, Levitz J, Garcia-Marcos M. Dissecting the molecular basis for the modulation of neurotransmitter GPCR signaling by GINIP. Structure 2024; 32:47-59.e7. [PMID: 37989308 PMCID: PMC10872408 DOI: 10.1016/j.str.2023.10.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 09/23/2023] [Accepted: 10/25/2023] [Indexed: 11/23/2023]
Abstract
It is well established that G-protein-coupled receptors (GPCRs) stimulated by neurotransmitters are critical for neuromodulation. Much less is known about how heterotrimeric G-protein (Gαβγ) regulation after receptor-mediated activation contributes to neuromodulation. Recent evidence indicates that the neuronal protein GINIP shapes GPCR inhibitory neuromodulation via a unique mechanism of G-protein regulation that controls pain and seizure susceptibility. However, the molecular basis of this mechanism remains ill-defined because the structural determinants of GINIP responsible for binding and regulating G proteins are not known. Here, we combined hydrogen-deuterium exchange mass spectrometry, computational structure predictions, biochemistry, and cell-based biophysical assays to demonstrate an effector-like binding mode of GINIP to Gαi. Specific amino acids of GINIP's PHD domain first loop are essential for G-protein binding and subsequent regulation of Gαi-GTP and Gβγ signaling upon neurotransmitter GPCR stimulation. In summary, these findings shed light onto the molecular basis for a post-receptor mechanism of G-protein regulation that fine-tunes inhibitory neuromodulation.
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Affiliation(s)
- Alex Luebbers
- Department of Biochemistry & Cell Biology, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
| | | | - Myles Zhou
- Department of Biochemistry & Cell Biology, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA
| | - Stephen J Eyles
- Mass Spectrometry Core Facility, Institute for Applied Life Sciences (IALS), University of Massachusetts Amherst, Amherst, MA 01003, USA
| | - Joshua Levitz
- Department of Biochemistry, Weill Cornell Medicine, New York, NY 10064, USA; Department of Psychiatry, Weill Cornell Medicine, New York, NY 10065, USA
| | - Mikel Garcia-Marcos
- Department of Biochemistry & Cell Biology, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA 02118, USA; Department of Biology, College of Arts & Sciences, Boston University, Boston, MA 02115, USA.
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14
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Tan W, Ma J, Fu J, Wu B, Zhu Z, Huang X, Du M, Wu C, Balawi E, Zhou Q, Zhang J, Liao Z. Transcriptomic and bioinformatics analysis of the mechanism by which erythropoietin promotes recovery from traumatic brain injury in mice. Neural Regen Res 2024; 19:171-179. [PMID: 37488864 PMCID: PMC10479836 DOI: 10.4103/1673-5374.374135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 02/04/2023] [Accepted: 03/11/2023] [Indexed: 07/26/2023] Open
Abstract
Recent studies have found that erythropoietin promotes the recovery of neurological function after traumatic brain injury. However, the precise mechanism of action remains unclear. In this study, we induced moderate traumatic brain injury in mice by intraperitoneal injection of erythropoietin for 3 consecutive days. RNA sequencing detected a total of 4065 differentially expressed RNAs, including 1059 mRNAs, 92 microRNAs, 799 long non-coding RNAs, and 2115 circular RNAs. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses revealed that the coding and non-coding RNAs that were differentially expressed after traumatic brain injury and treatment with erythropoietin play roles in the axon guidance pathway, Wnt pathway, and MAPK pathway. Constructing competing endogenous RNA networks showed that regulatory relationship between the differentially expressed non-coding RNAs and mRNAs. Because the axon guidance pathway was repeatedly enriched, the expression of Wnt5a and Ephb6, key factors in the axonal guidance pathway, was assessed. Ephb6 expression decreased and Wnt5a expression increased after traumatic brain injury, and these effects were reversed by treatment with erythropoietin. These findings suggest that erythropoietin can promote recovery of nerve function after traumatic brain injury through the axon guidance pathway.
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Affiliation(s)
- Weilin Tan
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jun Ma
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jiayuanyuan Fu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Biying Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ziyu Zhu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuekang Huang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Mengran Du
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Chenrui Wu
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ehab Balawi
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang Zhou
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jie Zhang
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhengbu Liao
- Department of Neurosurgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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15
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Liao W, Lee KZ. CDKL5-mediated developmental tuning of neuronal excitability and concomitant regulation of transcriptome. Hum Mol Genet 2023; 32:3276-3298. [PMID: 37688574 DOI: 10.1093/hmg/ddad149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/31/2023] [Accepted: 09/06/2023] [Indexed: 09/11/2023] Open
Abstract
Cyclin-dependent kinase-like 5 (CDKL5) is a serine-threonine kinase enriched in the forebrain to regulate neuronal development and function. Patients with CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition caused by mutations of CDKL5 gene, present early-onset epilepsy as the most prominent feature. However, spontaneous seizures have not been reported in mouse models of CDD, raising vital questions on the human-mouse differences and the roles of CDKL5 in early postnatal brains. Here, we firstly measured electroencephalographic (EEG) activities via a wireless telemetry system coupled with video-recording in neonatal mice. We found that mice lacking CDKL5 exhibited spontaneous epileptic EEG discharges, accompanied with increased burst activities and ictal behaviors, specifically at postnatal day 12 (P12). Intriguingly, those epileptic spikes disappeared after P14. We next performed an unbiased transcriptome profiling in the dorsal hippocampus and motor cortex of Cdkl5 null mice at different developmental timepoints, uncovering a set of age-dependent and brain region-specific alterations of gene expression in parallel with the transient display of epileptic activities. Finally, we validated multiple differentially expressed genes, such as glycine receptor alpha 2 and cholecystokinin, at the transcript or protein levels, supporting the relevance of these genes to CDKL5-regulated excitability. Our findings reveal early-onset neuronal hyperexcitability in mouse model of CDD, providing new insights into CDD etiology and potential molecular targets to ameliorate intractable neonatal epilepsy.
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Affiliation(s)
- Wenlin Liao
- Institute of Neuroscience, National Cheng-Chi University, Taipei 116, Taiwan
- Research Center for Mind, Brain and Learning, National Cheng-Chi University, Taipei 116, Taiwan
| | - Kun-Ze Lee
- Department of Biological Sciences, National Sun Yat-Sen University, No. 70, Lienhai Road, Kaohsiung 80424, Taiwan
- Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan
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16
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Metcalf CS. Brake Early: RGS14 in CA2 Limits Seizures and Oxidative Stress After SE. Epilepsy Curr 2023; 23:372-374. [PMID: 38269350 PMCID: PMC10805082 DOI: 10.1177/15357597231199343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2024] Open
Abstract
RGS14 Limits Seizure-Induced Mitochondrial Oxidative Stress and Pathology in Hippocampus Harbin NH, Lustberg DJ, Hurst C, Pare J, Crotty KM, Waters AL, Yeligar SM, Smith Y, Seyfried NT, Weinschenker D, Hepler JR. Neurobiol Dis. 2023;181:106128. doi:10.1016/j.nbd.2023.106128 . PMID: 37075948 RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. In these neurons, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies showed that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity, possibly affording protection to CA2 PCs. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show that the loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Our proteomics data show that the loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found that RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we unexpectedly found no differences in neuronal injury in CA2 PCs. However, we observed a striking and surprising lack of microgliosis in CA1 and CA2 of RGS14 KO compared to WT. Together, our data demonstrate a newly appreciated role for RGS14 in limiting intense seizure activity and pathology in hippocampus. Our findings are consistent with a model where RGS14 limits seizure onset and mortality and, after seizure, is upregulated to support mitochondrial function, prevent oxidative stress in CA2 PCs, and promote microglial activation in hippocampus.
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17
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DeBaker MC, Mitten EH, Rose TR, Marron Fernandez de Velasco E, Gao R, Lee AM, Wickman K. RGS6 negatively regulates inhibitory G protein signaling in dopamine neurons and positively regulates binge-like alcohol consumption in mice. Br J Pharmacol 2023; 180:2140-2155. [PMID: 36929333 PMCID: PMC10504421 DOI: 10.1111/bph.16071] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/02/2023] [Accepted: 03/13/2023] [Indexed: 03/18/2023] Open
Abstract
BACKGROUND AND PURPOSE Drugs of abuse, including alcohol, increase dopamine in the mesocorticolimbic system via actions on dopamine neurons in the ventral tegmental area (VTA). Increased dopamine transmission can activate inhibitory G protein signalling pathways in VTA dopamine neurons, including those controlled by GABAB and D2 receptors. Members of the R7 subfamily of regulator of G protein signalling (RGS) proteins can regulate inhibitory G protein signalling, but their influence on VTA dopamine neurons is unclear. Here, we investigated the influence of RGS6, an R7 RGS family memberthat has been implicated in the regulation of alcohol consumption in mice, on inhibitory G protein signalling in VTA dopamine neurons. EXPERIMENTAL APPROACH We used molecular, electrophysiological and genetic approaches to probe the impact of RGS6 on inhibitory G protein signalling in VTA dopamine neurons and on binge-like alcohol consumption in mice. KEY RESULTS RGS6 is expressed in adult mouse VTA dopamine neurons and it modulates inhibitory G protein signalling in a receptor-dependent manner, tempering D2 receptor-induced somatodendritic currents and accelerating deactivation of synaptically evoked GABAB receptor-dependent responses. RGS6-/- mice exhibit diminished binge-like alcohol consumption, a phenotype replicated in female (but not male) mice lacking RGS6 selectively in VTA dopamine neurons. CONCLUSIONS AND IMPLICATIONS RGS6 negatively regulates GABAB - and D2 receptor-dependent inhibitory G protein signalling pathways in mouse VTA dopamine neurons and exerts a sex-dependent positive influence on binge-like alcohol consumption in adult mice. As such, RGS6 may represent a new diagnostic and/or therapeutic target for alcohol use disorder.
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Affiliation(s)
- Margot C. DeBaker
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN
| | - Eric H. Mitten
- Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN
| | - Timothy R. Rose
- Department of Pharmacology, University of Minnesota, Minneapolis, MN
| | | | - Runbo Gao
- Department of Pharmacology, University of Minnesota, Minneapolis, MN
| | - Anna M. Lee
- Department of Pharmacology, University of Minnesota, Minneapolis, MN
| | - Kevin Wickman
- Department of Pharmacology, University of Minnesota, Minneapolis, MN
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18
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Pandey M, Zhang JH, Adikaram PR, Kittock C, Lue N, Awe A, Degner K, Jacob N, Staples J, Thomas R, Kohnen AB, Ganesan S, Kabat J, Chen CK, Simonds WF. Specific regulation of mechanical nociception by Gβ5 involves GABA-B receptors. JCI Insight 2023; 8:e134685. [PMID: 37219953 PMCID: PMC10371342 DOI: 10.1172/jci.insight.134685] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 05/19/2023] [Indexed: 05/24/2023] Open
Abstract
Mechanical, thermal, and chemical pain sensation is conveyed by primary nociceptors, a subset of sensory afferent neurons. The intracellular regulation of the primary nociceptive signal is an area of active study. We report here the discovery of a Gβ5-dependent regulatory pathway within mechanical nociceptors that restrains antinociceptive input from metabotropic GABA-B receptors. In mice with conditional knockout (cKO) of the gene that encodes Gβ5 (Gnb5) targeted to peripheral sensory neurons, we demonstrate the impairment of mechanical, thermal, and chemical nociception. We further report the specific loss of mechanical nociception in Rgs7-Cre+/- Gnb5fl/fl mice but not in Rgs9-Cre+/- Gnb5fl/fl mice, suggesting that Gβ5 might specifically regulate mechanical pain in regulator of G protein signaling 7-positive (Rgs7+) cells. Additionally, Gβ5-dependent and Rgs7-associated mechanical nociception is dependent upon GABA-B receptor signaling since both were abolished by treatment with a GABA-B receptor antagonist and since cKO of Gβ5 from sensory cells or from Rgs7+ cells potentiated the analgesic effects of GABA-B agonists. Following activation by the G protein-coupled receptor Mrgprd agonist β-alanine, enhanced sensitivity to inhibition by baclofen was observed in primary cultures of Rgs7+ sensory neurons harvested from Rgs7-Cre+/- Gnb5fl/fl mice. Taken together, these results suggest that the targeted inhibition of Gβ5 function in Rgs7+ sensory neurons might provide specific relief for mechanical allodynia, including that contributing to chronic neuropathic pain, without reliance on exogenous opioids.
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Affiliation(s)
- Mritunjay Pandey
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Jian-Hua Zhang
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Poorni R. Adikaram
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Claire Kittock
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Nicole Lue
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Adam Awe
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Katherine Degner
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Nirmal Jacob
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Jenna Staples
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Rachel Thomas
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Allison B. Kohnen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
| | - Sundar Ganesan
- Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Juraj Kabat
- Research Technologies Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland, USA
| | - Ching-Kang Chen
- Department of Molecular Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - William F. Simonds
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), Bethesda, Maryland, USA
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19
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Harbin NH, Lustberg DJ, Hurst C, Pare J, Crotty KM, Waters AL, Yeligar SM, Smith Y, Seyfried NT, Weinshenker D, Hepler JR. RGS14 limits seizure-induced mitochondrial oxidative stress and pathology in hippocampus. Neurobiol Dis 2023; 181:106128. [PMID: 37075948 PMCID: PMC10259180 DOI: 10.1016/j.nbd.2023.106128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 04/02/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023] Open
Abstract
RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. In these neurons, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies showed that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity, possibly affording protection to CA2 PCs. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show that the loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Our proteomics data show that the loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found that RGS14 KO dramatically increased 3- nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we unexpectedly found no differences in neuronal injury in CA2 PCs. However, we observed a striking and surprising lack of microgliosis in CA1 and CA2 of RGS14 KO compared to WT. Together, our data demonstrate a newly appreciated role for RGS14 in limiting intense seizure activity and pathology in hippocampus. Our findings are consistent with a model where RGS14 limits seizure onset and mortality and, after seizure, is upregulated to support mitochondrial function, prevent oxidative stress in CA2 PCs, and promote microglial activation in hippocampus.
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Affiliation(s)
- N H Harbin
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, 5001 Rollins Research Ctr, Atlanta, GA 30322, United States.
| | - D J Lustberg
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, United States
| | - C Hurst
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd, 4001 Rollins Research Center, Atlanta, GA 30322, United States.
| | - J Pare
- Emory National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30329, United States.
| | - K M Crotty
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, 1364 Clifton Road NE, Suite H-153, Atlanta, GA 30322, United States; Atlanta Veterans Affairs Health Care System, 1670 Clairmont Road, Decatur, GA 30033, United States.
| | - A L Waters
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, 5001 Rollins Research Ctr, Atlanta, GA 30322, United States.
| | - S M Yeligar
- Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, Emory University, 1364 Clifton Road NE, Suite H-153, Atlanta, GA 30322, United States; Atlanta Veterans Affairs Health Care System, 1670 Clairmont Road, Decatur, GA 30033, United States.
| | - Y Smith
- Emory National Primate Research Center, Emory University, 954, Gatewood Rd NE, Atlanta, GA 30329, United States; Department of Neurology, Emory University School of Medicine, 12 Executive Park Dr NE, Atlanta, GA, 30322, United States.
| | - N T Seyfried
- Department of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd, 4001 Rollins Research Center, Atlanta, GA 30322, United States.
| | - D Weinshenker
- Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Suite 301, Atlanta, GA 30322, United States.
| | - J R Hepler
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 1510 Clifton Rd, 5001 Rollins Research Ctr, Atlanta, GA 30322, United States.
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20
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Danaf J, da Silveira Scarpellini C, Montandon G. βγ G-proteins, but not regulators of G-protein signaling 4, modulate opioid-induced respiratory rate depression. Front Physiol 2023; 14:1043581. [PMID: 37089428 PMCID: PMC10117644 DOI: 10.3389/fphys.2023.1043581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 03/24/2023] [Indexed: 04/09/2023] Open
Abstract
Opioid medications are the mainstay of pain management but present substantial side-effects such as respiratory depression which can be lethal with overdose. Most opioid drugs, such as fentanyl, act on opioid receptors such as the G-protein-coupled µ-opioid receptors (MOR). G-protein-coupled receptors activate pertussis toxin-sensitive G-proteins to inhibit neuronal activity. Binding of opioid ligands to MOR and subsequent activation G proteins βγ is modulated by regulator of G-protein signaling (RGS). The roles of G-proteins βγ and RGS in MOR-mediated inhibition of the respiratory network are not known. Using rodent models to pharmacologically modulate G-protein signaling, we aim to determine the roles of βγ G-proteins and RGS4. We showed that inhibition of βγ G-proteins using gallein perfused in the brainstem circuits regulating respiratory depression by opioid drugs results in complete reversal of respiratory depression. Blocking of RGS4 using CCG55014 did not change the respiratory depression induced by MOR activation despite co-expression of RGS4 and MORs in the brainstem. Our results suggest that neuronal inhibition by opioid drugs is mediated by G-proteins, but not by RGS4, which supports the concept that βγ G-proteins could be molecular targets to develop opioid overdose antidotes without the risks of re-narcotization often found with highly potent opioid drugs. On the other hand, RGS4 mediates opioid analgesia, but not respiratory depression, and RGS4 may be molecular targets to develop pain therapies without respiratory liability.
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Affiliation(s)
- Jamil Danaf
- St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
| | | | - Gaspard Montandon
- St. Michael’s Hospital, Unity Health Toronto, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
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21
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Squitti R, Catalli C, Gigante L, Marianetti M, Rosari M, Mariani S, Bucossi S, Mastromoro G, Ventriglia M, Simonelli I, Tondolo V, Singh P, Kumar A, Pal A, Rongioletti M. Non-Ceruloplasmin Copper Identifies a Subtype of Alzheimer’s Disease (CuAD): Characterization of the Cognitive Profile and Case of a CuAD Patient Carrying an RGS7 Stop-Loss Variant. Int J Mol Sci 2023; 24:ijms24076377. [PMID: 37047347 PMCID: PMC10094789 DOI: 10.3390/ijms24076377] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 03/22/2023] [Accepted: 03/25/2023] [Indexed: 03/31/2023] Open
Abstract
Alzheimer’s disease (AD) is a type of dementia whose cause is incompletely defined. Copper (Cu) involvement in AD etiology was confirmed by a meta-analysis on about 6000 participants, showing that Cu levels were decreased in AD brain specimens, while Cu and non-bound ceruloplasmin Cu (non-Cp Cu) levels were increased in serum/plasma samples. Non-Cp Cu was advocated as a stratification add-on biomarker of a Cu subtype of AD (CuAD subtype). To further circumstantiate this concept, we evaluated non-Cp Cu reliability in classifying subtypes of AD based on the characterization of the cognitive profile. The stratification of the AD patients into normal AD (non-Cp Cu ≤ 1.6 µmol/L) and CuAD (non-Cp Cu > 1.6 µmol/L) showed a significant difference in executive function outcomes, even though patients did not differ in disease duration and severity. Among the Cu-AD patients, a 76-year-old woman showed significantly abnormal levels in the Cu panel and underwent whole exome sequencing. The CuAD patient was detected with possessing the homozygous (c.1486T > C; p.(Ter496Argext*19) stop-loss variant in the RGS7 gene (MIM*602517), which encodes for Regulator of G Protein Signaling 7. Non-Cp Cu as an add-on test in the AD diagnostic pathway can provide relevant information about the underlying pathological processes in subtypes of AD and suggest specific therapeutic options.
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Affiliation(s)
- Rosanna Squitti
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
- Correspondence: rosanna.squitti.fw.@fbf-isola.it or
| | - Claudio Catalli
- Osakidetza Basque Health Service, Department of Genetics, Cruces University Hospital, 48903 Barakaldo, Spain
- Neuromuscular Disorders Research Group, Biocruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain
| | - Laura Gigante
- Eurofins Genoma Group, Molecular Genetics Laboratory, 00138 Rome, Italy
| | - Massimo Marianetti
- Experimental Alzheimer Center, Fatebenefratelli Roman Province, 00189 Rome, Italy
| | - Mattia Rosari
- Experimental Alzheimer Center, Fatebenefratelli Roman Province, 00189 Rome, Italy
| | - Stefania Mariani
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
| | - Serena Bucossi
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
| | - Gioia Mastromoro
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
| | - Mariacarla Ventriglia
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
| | - Ilaria Simonelli
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
| | - Vincenzo Tondolo
- Digestive and Colorectal Surgery, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
- Digestive Surgery Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
| | - Parminder Singh
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh 160025, India
| | - Ashok Kumar
- Centre for Systems Biology and Bioinformatics, Panjab University, Chandigarh 160025, India
| | - Amit Pal
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS), Kalyani 741245, India
| | - Mauro Rongioletti
- Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina—Gemelli Isola, 00186 Rome, Italy
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22
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Montanez-Miranda C, Bramlett SN, Hepler JR. RGS14 expression in CA2 hippocampus, amygdala, and basal ganglia: Implications for human brain physiology and disease. Hippocampus 2023; 33:166-181. [PMID: 36541898 PMCID: PMC9974931 DOI: 10.1002/hipo.23492] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 11/09/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
RGS14 is a multifunctional scaffolding protein that is highly expressed within postsynaptic spines of pyramidal neurons in hippocampal area CA2. Known roles of RGS14 in CA2 include regulating G protein, H-Ras/ERK, and calcium signaling pathways to serve as a natural suppressor of synaptic plasticity and postsynaptic signaling. RGS14 also shows marked postsynaptic expression in major structures of the limbic system and basal ganglia, including the amygdala and both the ventral and dorsal subdivisions of the striatum. In this review, we discuss the signaling functions of RGS14 and its role in postsynaptic strength (long-term potentiation) and spine structural plasticity in CA2 hippocampal neurons, and how RGS14 suppression of plasticity impacts linked behaviors such as spatial learning, object memory, and fear conditioning. We also review RGS14 expression in the limbic system and basal ganglia and speculate on its possible roles in regulating plasticity in these regions, with a focus on behaviors related to emotion and motivation. Finally, we explore the functional implications of RGS14 in various brain circuits and speculate on its possible roles in certain disease states such as hippocampal seizures, addiction, and anxiety disorders.
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Affiliation(s)
| | | | - John R. Hepler
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322-3090
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23
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Harbin NH, Lustberg DJ, Hurst C, Pare JF, Crotty KM, Waters AL, Yeligar SM, Smith Y, Seyfried NT, Weinshenker D, Hepler JR. RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.01.526349. [PMID: 36778349 PMCID: PMC9915580 DOI: 10.1101/2023.02.01.526349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. There, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies show that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Utilizing proteomics, we saw loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro . As a readout of oxidative stress, we found RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we observed worse neuronal injury in area CA3 (but none in CA2 or CA1), and a lack of microgliosis in CA1 and CA2 compared to WT. Together, our data demonstrates a newly appreciated neuroprotective role for RGS14 against intense seizure activity in hippocampus. Our findings are consistent with a model where, after seizure, RGS14 is upregulated to support mitochondrial function and prevent oxidative stress in CA2 PCs, limit seizure onset and hippocampal neuronal injury, and promote microglial activation in hippocampus.
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24
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Sun JKL, Wu D, Wong GCN, Lau TM, Yang M, Hart RP, Kwan KM, Chan HYE, Chow HM. Chronic alcohol metabolism results in DNA repair infidelity and cell cycle-induced senescence in neurons. Aging Cell 2023; 22:e13772. [PMID: 36691110 PMCID: PMC9924945 DOI: 10.1111/acel.13772] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 10/18/2022] [Accepted: 12/20/2022] [Indexed: 01/25/2023] Open
Abstract
Chronic binge-like drinking is a risk factor for age-related dementia, however, the lasting and irreversible effect of alcohol on the brain remains elusive. Transcriptomic changes in brain cortices revealed pro-ageing hallmarks upon chronic ethanol exposure and these changes predominantly occur in neurons. The changes are attributed to a prioritized ethyl alcohol oxidation in these cells via the NADPH-dependent cytochrome pathway. This hijacks the folate metabolism of the 1-carbon network which supports the pathway choice of DNA repair via the non-cell cycle-dependent mismatch repair networks. The lost-in-function of such results in the de-inactivation of the less preferred cell cycle-dependent homologous recombination (HR) repair, forcing these post-mitotic cells to re-engage in a cell cycle-like process. However, mature neurons are post-mitotic. Therefore, instead of successfully completing a full round of cell cycle which is necessary for the completion of HR-mediated repair; these cells are arrested at checkpoints. The resulting persistence of repair intermediates induces and promotes the nuclear accumulation of p21 and cyclin B-a trigger for permanent cell cycle exits and irreversible senescence response. Supplementation of bioactive 5-methyl tetrahydrofolate simultaneously at times with ethyl alcohol exposure supports the fidelity of the 1-carbon network and hence the activity of the mismatch repair. This prevents aberrant and irreversible cell cycle re-entry and senescence events of neurons. Together, our findings offer a direct connection between binge-drinking behaviour and its irreversible impact on the brain, which makes it a potential risk factor for dementia.
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Affiliation(s)
- Jacquelyne Ka-Li Sun
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Deng Wu
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Genper Chi-Ngai Wong
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Tsun-Ming Lau
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Meigui Yang
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Ronald P Hart
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey, USA
| | - Kin-Ming Kwan
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Centre for Cell and Developmental Biology, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Ho Yin Edwin Chan
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Gerald Choa Neuroscience Centre, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Hei-Man Chow
- School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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25
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Lepiarczyk E, Paukszto Ł, Wiszpolska M, Łopieńska-Biernat E, Bossowska A, Majewski MK, Majewska M. Molecular Influence of Resiniferatoxin on the Urinary Bladder Wall Based on Differential Gene Expression Profiling. Cells 2023; 12:cells12030462. [PMID: 36766804 PMCID: PMC9914288 DOI: 10.3390/cells12030462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/04/2023] Open
Abstract
Resiniferatoxin (RTX) is a potent capsaicin analog used as a drug for experimental therapy to treat neurogenic disorders associated with enhanced nociceptive transmission, including lower urinary tract symptoms. The present study, for the first time, investigated the transcriptomic profile of control and RTX-treated porcine urinary bladder walls. We applied multistep bioinformatics and discovered 129 differentially expressed genes (DEGs): 54 upregulated and 75 downregulated. Metabolic pathways analysis revealed five significant Kyoto Encyclopedia of Genes and Genomes (KEGG) items ('folate biosynthesis', 'metabolic pathways', 'sulfur relay system', 'sulfur metabolism' and 'serotonergic synapse') that were altered after RTX intravesical administration. A thorough analysis of the detected DEGs indicated that RTX treatment influenced the signaling pathways regulating nerve growth, myelination, axon specification, and elongation. Many of the revealed DEGs are involved in the nerve degeneration process; however, some of them were implicated in the initiation of neuroprotective mechanisms. Interestingly, RTX intravesical installation was followed by changes in the expression of genes involved in synaptic plasticity and neuromodulation, including 5-HT, H2S, glutamate, and GABA transmission. The obtained results suggest that the toxin may exert a therapeutic, antinociceptive effect not only by acting on TRPV1 receptors.
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Affiliation(s)
- Ewa Lepiarczyk
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland
- Correspondence: ; Tel.: +48-89-524-53-34; Fax: +48-89-524-53-07
| | - Łukasz Paukszto
- Department of Botany and Nature Protection, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-727 Olsztyn, Poland
| | - Marta Wiszpolska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland
| | - Elżbieta Łopieńska-Biernat
- Department of Biochemistry, Faculty of Biology and Biotechnology, University of Warmia and Mazury in Olsztyn, 10-719 Olsztyn, Poland
| | - Agnieszka Bossowska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland
| | - Mariusz Krzysztof Majewski
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland
| | - Marta Majewska
- Department of Human Physiology and Pathophysiology, School of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, 10-082 Olsztyn, Poland
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26
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Molecular Landscape of Tourette's Disorder. Int J Mol Sci 2023; 24:ijms24021428. [PMID: 36674940 PMCID: PMC9865021 DOI: 10.3390/ijms24021428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/29/2022] [Accepted: 01/01/2023] [Indexed: 01/12/2023] Open
Abstract
Tourette's disorder (TD) is a highly heritable childhood-onset neurodevelopmental disorder and is caused by a complex interplay of multiple genetic and environmental factors. Yet, the molecular mechanisms underlying the disorder remain largely elusive. In this study, we used the available omics data to compile a list of TD candidate genes, and we subsequently conducted tissue/cell type specificity and functional enrichment analyses of this list. Using genomic data, we also investigated genetic sharing between TD and blood and cerebrospinal fluid (CSF) metabolite levels. Lastly, we built a molecular landscape of TD through integrating the results from these analyses with an extensive literature search to identify the interactions between the TD candidate genes/proteins and metabolites. We found evidence for an enriched expression of the TD candidate genes in four brain regions and the pituitary. The functional enrichment analyses implicated two pathways ('cAMP-mediated signaling' and 'Endocannabinoid Neuronal Synapse Pathway') and multiple biological functions related to brain development and synaptic transmission in TD etiology. Furthermore, we found genetic sharing between TD and the blood and CSF levels of 39 metabolites. The landscape of TD not only provides insights into the (altered) molecular processes that underlie the disease but, through the identification of potential drug targets (such as FLT3, NAALAD2, CX3CL1-CX3CR1, OPRM1, and HRH2), it also yields clues for developing novel TD treatments.
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27
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Alhowail A. Mechanisms Underlying Cognitive Impairment Induced by Prenatal Alcohol Exposure. Brain Sci 2022; 12:brainsci12121667. [PMID: 36552126 PMCID: PMC9775935 DOI: 10.3390/brainsci12121667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 11/29/2022] [Accepted: 12/02/2022] [Indexed: 12/07/2022] Open
Abstract
Alcohol is one of the most commonly used illicit substances among pregnant women. Clinical and experimental studies have revealed that prenatal alcohol exposure affects fetal brain development and ultimately results in the persistent impairment of the offspring's cognitive functions. Despite this, the rate of alcohol use among pregnant women has been progressively increasing. Various aspects of human and animal behavior, including learning and memory, are dependent on complex interactions between multiple mechanisms, such as receptor function, mitochondrial function, and protein kinase activation, which are especially vulnerable to alterations during the developmental period. Thus, the exploration of the mechanisms that are altered in response to prenatal alcohol exposure is necessary to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral impairments manifest following alcohol abuse during pregnancy. There is evidence that prenatal alcohol exposure results in vast alterations in mechanisms such as long-term potentiation, mitochondrial function, and protein kinase activation in the brain of offspring. However, to the best of our knowledge, there are very few recent reviews that focus on the cognitive effects of prenatal alcohol exposure and the associated mechanisms. Therefore, in this review, we aim to provide a comprehensive summary of the recently reported alterations to various mechanisms following alcohol exposure during pregnancy, and to draw potential associations with behavioral changes in affected offspring.
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Affiliation(s)
- Ahmad Alhowail
- Department of Pharmacology and Toxicology, College of Pharmacy, Qassim University, Al Qassim 51452, Saudi Arabia
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28
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Co-Expression of Adaptor Protein FAM159B with Different Markers for Neuroendocrine Cells: An Immunocytochemical and Immunohistochemical Study. Int J Mol Sci 2022; 23:ijms232113503. [DOI: 10.3390/ijms232113503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 10/23/2022] [Accepted: 11/03/2022] [Indexed: 11/06/2022] Open
Abstract
Little is known about the adaptor protein FAM159B. Recently, FAM159B was shown to be particularly expressed in neuroendocrine cells and tissues, such as pancreatic islets and neuroendocrine cells of the bronchopulmonary and gastrointestinal tracts, as well as in different types of neuroendocrine tumours. To gain insights into possible interactions of FAM159B with other proteins and/or receptors, we analysed the co-expression of FAM159B and various neuroendocrine-specific markers in the cancer cell lines BON-1, PC-3, NCI-h82, OH-1, and A431 and also in human pancreatic tissues and pancreatic neuroendocrine tumours. The markers included prominent markers of neuroendocrine differentiation, such as chromogranin A (CgA), neuron-specific enolase (NSE), synaptophysin (SYP), insulinoma-associated protein 1 (INSM1), neural cell adhesion molecule 1 (NCAM1), serotonin (5-HT), somatostatin-14/28 (SST), and several receptors that are typically expressed by neuroendocrine cells, such as dopamine receptor 2 (D2R), somatostatin receptor (SSTR) 1, 2, 3, 4 and 5, and regulator of G-protein signalling 9 (RGS9). FAM159B was expressed evenly throughout the cytosol in all five cancer cell lines. Immunocytochemical and immunohistochemical analyses revealed co-expression of FAM159B with SYP, INSM1, RGS9, D2R, SSTR2, SSTR3, SSTR4, and SSTR5 and strong overlapping co-localisation with NSE. Double-labelling and co-immunoprecipitation Western blot analyses confirmed a direct association between FAM159B and NSE. These results suggest the involvement of FAM159B in several intracellular signalling pathways and a direct or indirect influence on diverse membrane proteins and receptors.
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29
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Zhao A, Jin H, Fan G, Li Y, Li C, Li Q, Ma X, Zhao T, Sun S, Liu S, Gao Y, Qi S. Inhibition of the expression of rgs-3 alleviates propofol-induced decline in learning and memory in Caenorhabditis elegans. CNS Neurosci Ther 2022; 29:306-316. [PMID: 36284438 PMCID: PMC9804065 DOI: 10.1111/cns.14004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 09/28/2022] [Accepted: 09/30/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Exposure to anesthesia leads to extensive neurodegeneration and long-term cognitive deficits in the developing brain. Caenorhabditis elegans also shows persistent behavioral changes during development after exposure to anesthetics. Clinical and rodent studies have confirmed that altered expression of the regulators of G protein signaling (RGS) in the nervous system is a factor contributing to neurodegenerative and psychological diseases. Evidence from preclinical studies has suggested that RGS controls drug-induced plasticity, including morphine tolerance and addiction. This study aimed to observe the effect of propofol exposure in the neurodevelopmental stage on learning and memory in the L4 stage and to study whether this effect is related to changes in rgs-3 expression. METHODS Caenorhabditis elegans were exposed to propofol at the L1 stage, and learning and memory abilities were observed at the L4 stage. The expression of rgs-3 and the nuclear distribution of EGL-4 were determined to study the relevant mechanisms. Finally, RNA interference was performed on rgs-3-expressing cells after propofol exposure. Then, we observed their learning and memory abilities. RESULTS Propofol time- and dose-dependently impaired the learning capacity. Propofol induced a decline in non-associative and associative long-term memory, rgs-3 upregulation, and a failure of nuclear accumulation of EGL-4/PKG in AWC neurons. Inhibition of rgs-3 could alleviate the propofol-induced changes. CONCLUSION Inhibition of the expression of rgs-3 alleviated propofol-induced learning and memory deficits in Caenorhabditis elegans.
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Affiliation(s)
- Ayang Zhao
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Hongjiang Jin
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Guibo Fan
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yan Li
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Chenglong Li
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Qi Li
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Xiaofei Ma
- Department of ICUThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Tianyang Zhao
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Siqi Sun
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Shuai Liu
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Yueyue Gao
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
| | - Sihua Qi
- Department of AnesthesiologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinChina
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30
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Rahman MM, Islam MR, Mim SA, Sultana N, Chellappan DK, Dua K, Kamal MA, Sharma R, Emran TB. Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:8425640. [PMID: 36187336 PMCID: PMC9519337 DOI: 10.1155/2022/8425640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022]
Abstract
G protein-coupled receptors (GPCRs) are intricately involved in the conversion of extracellular feedback to intracellular responses. These specialized receptors possess a crucial role in neurological and psychiatric disorders. Most nonsensory GPCRs are active in almost 90% of complex brain functions. At the time of receptor phosphorylation, a GPCR pathway is essentially activated through a G protein signaling mechanism via a G protein-coupled receptor kinase (GRK). Dopamine, an important neurotransmitter, is primarily involved in the pathophysiology of several CNS disorders; for instance, bipolar disorder, schizophrenia, Parkinson's disease, and ADHD. Since dopamine, acetylcholine, and glutamate are potent neuropharmacological targets, dopamine itself has potential therapeutic effects in several CNS disorders. GPCRs essentially regulate brain functions by modulating downstream signaling pathways. GPR6, GPR52, and GPR8 are termed orphan GPCRs because they colocalize with dopamine D1 and D2 receptors in neurons of the basal ganglia, either alone or with both receptors. Among the orphan GPCRs, the GPR52 is recognized for being an effective psychiatric receptor. Various antipsychotics like aripiprazole and quetiapine mainly target GPCRs to exert their actions. One of the most important parts of signal transduction is the regulation of G protein signaling (RGS). These substances inhibit the activation of the G protein that initiates GPCR signaling. Developing a combination of RGS inhibitors with GPCR agonists may prove to have promising therapeutic potential. Indeed, several recent studies have suggested that GPCRs represent potentially valuable therapeutic targets for various psychiatric disorders. Molecular biology and genetically modified animal model studies recommend that these enriched GPCRs may also act as potential therapeutic psychoreceptors. Neurotransmitter and neuropeptide GPCR malfunction in the frontal cortex and limbic-related regions, including the hippocampus, hypothalamus, and brainstem, is likely responsible for the complex clinical picture that includes cognitive, perceptual, emotional, and motor symptoms. G protein and GPCR-mediated signaling play a critical role in developing new treatment options for mental health issues, and this study is aimed at offering a thorough picture of that involvement. For patients who are resistant to current therapies, the development of new drugs that target GPCR signaling cascades remains an interesting possibility. These discoveries might serve as a fresh foundation for the creation of creative methods for pharmacologically useful modulation of GPCR function.
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Affiliation(s)
- Md. Mominur Rahman
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Md. Rezaul Islam
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Sadia Afsana Mim
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Nasrin Sultana
- Department of Pharmacy, Faculty of Allied Health Sciences, Daffodil International University, Dhaka 1207, Bangladesh
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil, 57000 Kuala Lumpur, Malaysia
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Mohammad Amjad Kamal
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041 Sichuan, China
- King Fahd Medical Research Center, King Abdulaziz University, Saudi Arabia
- Enzymoics, Novel Global Community Educational Foundation, Australia
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, Banaras Hindu University, Varanasi, 221005 Uttar Pradesh, India
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
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Fullerton EF, Karom MC, Streicher JM, Young LJ, Murphy AZ. Age-Induced Changes in µ-Opioid Receptor Signaling in the Midbrain Periaqueductal Gray of Male and Female Rats. J Neurosci 2022; 42:6232-6242. [PMID: 35790399 PMCID: PMC9374133 DOI: 10.1523/jneurosci.0355-22.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 04/08/2022] [Accepted: 04/16/2022] [Indexed: 11/21/2022] Open
Abstract
Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. The present study investigated the impact of advanced age and biological sex on opioid signaling in the ventrolateral periaqueductal gray (vlPAG) in the presence of chronic inflammatory pain. Assays measuring µ-opioid receptor (MOR) radioligand binding, GTPγS binding, receptor phosphorylation, cAMP inhibition, and regulator of G-protein signaling (RGS) protein expression were performed on vlPAG tissue from adult (2-3 months) and aged (16-18 months) male and female rats. Persistent inflammatory pain was induced by intraplantar injection of complete Freund's adjuvant (CFA). Adult males exhibited the highest MOR binding potential (BP) and highest G-protein activation (activation efficiency ratio) in comparison to aged males and females (adult and aged). No impact of advanced age or sex on MOR phosphorylation state was observed. DAMGO-induced cAMP inhibition was highest in the vlPAG of adult males compared with aged males and females (adult and aged). vlPAG levels of RGS4 and RGS9-2, critical for terminating G-protein signaling, were assessed using RNAscope. Adult rats (both males and females) exhibited lower levels of vlPAG RGS4 and RGS9-2 mRNA expression compared with aged males and females. The observed age-related reductions in vlPAG MOR BP, G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in RGS4 and RGS9-2 vlPAG expression, provide potential mechanisms whereby the potency of opioids is decreased in the aged population.SIGNIFICANCE STATEMENT Opioids have decreased analgesic potency (but not efficacy) in aged rodents compared with adults; however, the neural mechanisms underlying this attenuated response are not yet known. In the present study, we observed age-related reductions in ventrolateral periaqueductal gray (vlPAG) µ-opioid receptor (MOR) binding potential (BP), G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in regulator of G-protein signaling (RGS)4 and RGS9-2 vlPAG expression, providing potential mechanisms whereby the potency of opioids is decreased in the aged population. These coordinated decreases in opioid receptor signaling may explain the previously reported reduced potency of opioids to produce pain relief in females and aged rats.
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Affiliation(s)
- Evan F Fullerton
- Neuroscience Institute, Georgia State University, Atlanta, Georgia 30303
| | - Mary C Karom
- Neuroscience Institute, Georgia State University, Atlanta, Georgia 30303
| | - John M Streicher
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724
| | - Larry J Young
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Anne Z Murphy
- Neuroscience Institute, Georgia State University, Atlanta, Georgia 30303
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Hyun SA, Ko MY, Jang S, Lee BS, Rho J, Kim KK, Kim WY, Ka M. Bisphenol-A impairs synaptic formation and function by RGS4-mediated negative regulation of BDNF/NTRK2 signaling in the cerebral cortex. Dis Model Mech 2022; 15:276081. [PMID: 35781563 PMCID: PMC9346518 DOI: 10.1242/dmm.049177] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 06/06/2022] [Indexed: 12/02/2022] Open
Abstract
Bisphenol-A (BPA) is a representative endocrine disruptor, widely used in a variety of products including plastics, medical equipment and receipts. Hence, most people are exposed to BPA via the skin, digestive system or inhalation in everyday life. Furthermore, BPA crosses the blood–brain barrier and is linked to multiple neurological dysfunctions found in neurodegenerative and neuropsychological disorders. However, the mechanisms underlying BPA-associated neurological dysfunctions remain poorly understood. Here, we report that BPA exposure alters synapse morphology and function in the cerebral cortex. Cortical pyramidal neurons treated with BPA showed reduced size and number of dendrites and spines. The density of excitatory synapses was also decreased by BPA treatment. More importantly, we found that BPA disrupted normal synaptic transmission and cognitive behavior. RGS4 and its downstream BDNF/NTRK2 pathway appeared to mediate the effect of BPA on synaptic and neurological function. Our findings provide molecular mechanistic insights into anatomical and physiological neurotoxic consequences related to a potent endocrine modifier. Summary: Bisphenol-A (BPA) disrupts normal synaptic transmission and cognitive behavior in mice. Rgs4 transcription factor and its downstream BDNF/NTRK2 pathway appear to mediate the effect of BPA on synaptic and neurological function.
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Affiliation(s)
- Sung-Ae Hyun
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, KRICT, Daejeon 34114, Republic of Korea.,Department of Biochemistry, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Moon Yi Ko
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, KRICT, Daejeon 34114, Republic of Korea.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Sumi Jang
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, KRICT, Daejeon 34114, Republic of Korea
| | - Byoung-Seok Lee
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, KRICT, Daejeon 34114, Republic of Korea
| | - Jaerang Rho
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Kee K Kim
- Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 34134, Republic of Korea
| | - Woo-Yang Kim
- Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Minhan Ka
- Department of Advanced Toxicology Research, Korea Institute of Toxicology, KRICT, Daejeon 34114, Republic of Korea
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Mohanta SK, Peng L, Li Y, Lu S, Sun T, Carnevale L, Perrotta M, Ma Z, Förstera B, Stanic K, Zhang C, Zhang X, Szczepaniak P, Bianchini M, Saeed BR, Carnevale R, Hu D, Nosalski R, Pallante F, Beer M, Santovito D, Ertürk A, Mettenleiter TC, Klupp BG, Megens RTA, Steffens S, Pelisek J, Eckstein HH, Kleemann R, Habenicht L, Mallat Z, Michel JB, Bernhagen J, Dichgans M, D'Agostino G, Guzik TJ, Olofsson PS, Yin C, Weber C, Lembo G, Carnevale D, Habenicht AJR. Neuroimmune cardiovascular interfaces control atherosclerosis. Nature 2022; 605:152-159. [PMID: 35477759 DOI: 10.1038/s41586-022-04673-6] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 01/31/2022] [Indexed: 02/08/2023]
Abstract
Atherosclerotic plaques develop in the inner intimal layer of arteries and can cause heart attacks and strokes1. As plaques lack innervation, the effects of neuronal control on atherosclerosis remain unclear. However, the immune system responds to plaques by forming leukocyte infiltrates in the outer connective tissue coat of arteries (the adventitia)2-6. Here, because the peripheral nervous system uses the adventitia as its principal conduit to reach distant targets7-9, we postulated that the peripheral nervous system may directly interact with diseased arteries. Unexpectedly, widespread neuroimmune cardiovascular interfaces (NICIs) arose in mouse and human atherosclerosis-diseased adventitia segments showed expanded axon networks, including growth cones at axon endings near immune cells and media smooth muscle cells. Mouse NICIs established a structural artery-brain circuit (ABC): abdominal adventitia nociceptive afferents10-14 entered the central nervous system through spinal cord T6-T13 dorsal root ganglia and were traced to higher brain regions, including the parabrachial and central amygdala neurons; and sympathetic efferent neurons projected from medullary and hypothalamic neurons to the adventitia through spinal intermediolateral neurons and both coeliac and sympathetic chain ganglia. Moreover, ABC peripheral nervous system components were activated: splenic sympathetic and coeliac vagus nerve activities increased in parallel to disease progression, whereas coeliac ganglionectomy led to the disintegration of adventitial NICIs, reduced disease progression and enhanced plaque stability. Thus, the peripheral nervous system uses NICIs to assemble a structural ABC, and therapeutic intervention in the ABC attenuates atherosclerosis.
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Affiliation(s)
- Sarajo K Mohanta
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
| | - Li Peng
- Department of Cardiovascular Internal Medicine, Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Yuanfang Li
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Shu Lu
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Ting Sun
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Lorenzo Carnevale
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy
| | - Marialuisa Perrotta
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy.,Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Zhe Ma
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Benjamin Förstera
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU), Munich, Germany
| | - Karen Stanic
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU), Munich, Germany
| | - Chuankai Zhang
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Xi Zhang
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Piotr Szczepaniak
- Department of Internal and Agricultural Medicine, Jagiellonian University Collegium Medicum, Krakow, Poland
| | - Mariaelvy Bianchini
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Borhan R Saeed
- Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Raimondo Carnevale
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy
| | - Desheng Hu
- Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany
| | - Ryszard Nosalski
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Fabio Pallante
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy
| | - Michael Beer
- Department for Information Technology, University of Jena, Jena University Hospital, Jena, Germany
| | - Donato Santovito
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.,Institute for Genetic and Biomedical Research, Unit of Milan, National Research Council, Milan, Italy
| | - Ali Ertürk
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU), Munich, Germany
| | - Thomas C Mettenleiter
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
| | - Barbara G Klupp
- Institute of Molecular Virology and Cell Biology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany
| | - Remco T A Megens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.,Department of Biomedical Engineering, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Sabine Steffens
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Jaroslav Pelisek
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.,Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
| | - Hans-Henning Eckstein
- Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Robert Kleemann
- Department of Metabolic Health Research, The Netherlands Organization for Applied Scientific Research (TNO), Leiden, The Netherlands.,Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - Livia Habenicht
- II. Medizinische Klinik und Poliklinik, Technische Universität München, Klinikum rechts der Isar, Munich, Germany
| | - Ziad Mallat
- Department of Medicine, Division of Cardiovascular Medicine, University of Cambridge, Cambridge, UK
| | - Jean-Baptiste Michel
- Laboratory for Vascular Translational Science, INSERM UMRS 1148, University Paris Diderot (P7), GH Bichat-Claude Bernard, Paris, France
| | - Jürgen Bernhagen
- German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.,Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Martin Dichgans
- Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität Munich (LMU), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Giuseppe D'Agostino
- Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Tomasz J Guzik
- Department of Internal and Agricultural Medicine, Jagiellonian University Collegium Medicum, Krakow, Poland.,Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Peder S Olofsson
- Laboratory of Immunobiology, Center for Bioelectronic Medicine, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Changjun Yin
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
| | - Christian Weber
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.,Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands
| | - Giuseppe Lembo
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy.,Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Daniela Carnevale
- Department of Angiocardioneurology and Translational Medicine, IRCCS Neuromed, Pozzilli, Italy.,Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Andreas J R Habenicht
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München (LMU), Munich, Germany. .,German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
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Ren W, Jin W, Liang Z. Construction and Validation of an Immune-Related Risk Score Model for Survival Prediction in Glioblastoma. Front Neurol 2022; 13:832944. [PMID: 35370869 PMCID: PMC8965766 DOI: 10.3389/fneur.2022.832944] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 01/20/2022] [Indexed: 12/12/2022] Open
Abstract
BackgroundAs one of the most important brain tumors, glioblastoma (GBM) has a poor prognosis, especially in adults. Immune-related genes (IRGs) and immune cell infiltration are responsible for the pathogenesis of GBM. This study aimed to identify new tumor markers to predict the prognosis of patients with GBM.MethodsThe Cancer Genome Atlas (TCGA) database and ImmPort database were used for model construction. The Wilcoxon rank-sum test was applied to identify the differentially expressed IRGs (DEIRGs) between the GBM and normal samples. Univariate Cox regression analysis and Kaplan–Meier analysis was performed to investigate the relationship between each DEIRG and overall survival. Next, multivariate Cox regression analysis was exploited to further explore the prognostic potential of DEIRGs. A risk-score model was constructed based on the above results. The area under the curve (AUC) values were calculated to assess the effect of the model prediction. Furthermore, the Chinese Glioma Genome Atlas (CGGA) dataset was used for model validation. STRING database and functional enrichment analysis were used for exploring the gene interactions and the underlying functions and pathways. The CIBERSORT algorithm was used for correlation analysis of the marker genes and the tumor-infiltrating immune cells.ResultsThere were 198 DEIRGs in GBM, including 153 upregulated genes and 45 downregulated genes. Seven marker genes (LYNX1, PRELID1P4, MMP9, TCF12, RGS14, RUNX1, and CCR2) were filtered out by sequential screening for DEIRGs. The regression coefficients (0.0410, 1.335, 0.005, −0.021, 0.123, 0.142, and −0.329) and expression data of the marker genes were used to construct the model. The AUC values for 1, 2, and 3 years were 0.744, 0.737, and 0.749 in the TCGA–GBM cohort and 0.612, 0.602, and 0.594 in the CGGA-GBM cohort, respectively, which indicated a high predictive power. The results of enrichment analysis revealed that these genes were enriched in the activation of T cell and cytokine receptor interaction pathways. The interaction network map demonstrated a close relationship between the marker genes MMP9 and CCR2. Infiltration analysis of the immune cells showed that dendritic cells (DCs) could identify GBM, while LYNX1, RUNX1, and CCR2 were significantly positively correlated with DCs expression.ConclusionThis study analyzed the expression of IRGs in GBM and identified seven marker genes for the construction of an immune-related risk score model. These marker genes were found to be associated with DCs and were enriched in similar immune response pathways. These findings are likely to provide new insights for the immunotherapy of patients with GBM.
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Affiliation(s)
- Wei Ren
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Weifeng Jin
- School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Zehua Liang
- School of Humanities and Management, Zhejiang Chinese Medical University, Hangzhou, China
- *Correspondence: Zehua Liang
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D'Souza MS, Seeley SL, Emerson N, Rose-Malkamaki MJ, Ho SP, Tsai YC, Kuo H, Huan CY, Rorabaugh BR. Attenuation of nicotine-induced rewarding and antidepressant-like effects in male and female mice lacking regulator of G-protein signaling 2. Pharmacol Biochem Behav 2022; 213:173338. [PMID: 35038444 DOI: 10.1016/j.pbb.2022.173338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 11/28/2022]
Abstract
Nicotine-induced rewarding and mood altering effects contribute to the continued use of nicotine and the subsequent development of nicotine dependence. The goal of this study was to assess the role of two specific regulators of G-protein signaling (RGS) proteins namely RGS2 and RGS4 in the above described effects of nicotine. Male and female mice lacking either RGS2 (RGS2 KO) or RGS4 (RGS4 KO), and their respective wildtype (WT) littermates were used in this study. The rewarding effects of nicotine (0.5 mg/kg, base; s.c.) were assessed using the conditioned place preference model. Nicotine-induced anxiolytic-like (0.1 mg/kg, base; i.p.) and antidepressant-like (1 mg/kg, base; i.p.) effects were assessed using the elevated plus maze and tail suspension test, respectively. We also assessed effects of nicotine (0, 0.05, 0.1 & 0.5 mg/kg, base; s.c.) on spontaneous locomotor activity. Nicotine-induced rewarding and antidepressant-like effects were observed in both male and female RGS2 WT mice, but not in mice lacking RGS2 compared to respective controls. In contrast, nicotine-induced rewarding and antidepressant-like effects were observed in both male and female mice lacking RGS4 and their WT littermates. Interestingly, deletion of RGS4 facilitated antidepressant-like effect of nicotine in male, but not female mice compared to respective WT littermates. Nicotine-induced anxiolytic-like effect was not influenced by deletion of either RGS2 or RGS4, irrespective of sex. Nicotine (0.5 mg/kg) decreased locomotor activity in both WT and KO mice compared to respective saline, irrespective of genotype and sex. Taken together, these data provide evidence that RGS2, but not RGS4, plays a role in mediating the rewarding and antidepressant-like effects of nicotine. Further research is required to explore the role of RGS2 after chronic exposure to nicotine.
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Affiliation(s)
- Manoranjan S D'Souza
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States.
| | - Sarah L Seeley
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Nate Emerson
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Madison J Rose-Malkamaki
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Sheng-Ping Ho
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Yi-Chih Tsai
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Henry Kuo
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Ching-Yu Huan
- Department of Pharmaceutical and Biomedical Sciences, The Raabe College of Pharmacy, Ohio Northern University, 525 S Main Street, Ada, OH 45810, United States
| | - Boyd R Rorabaugh
- Department of Pharmaceutical Sciences, School of Pharmacy, Marshall University, 1 John Marshall Drive, Huntington, WV 25755, United States
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Francisco RD, Fernando V, Norma E, Madai ME, Marcelo B. Glial changes in schizophrenia: Genetic and epigenetic approach. Indian J Psychiatry 2022; 64:3-12. [PMID: 35400734 PMCID: PMC8992743 DOI: 10.4103/indianjpsychiatry.indianjpsychiatry_104_21] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 10/24/2021] [Accepted: 12/23/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Schizophrenia (SCZ) is a severe mental illness that affects one percent of the population, affecting how people think, feel, and behave. Evidence suggests glial cell alteration and some researchers have found genetic risk loci and epigenetic marks that may regulate glia-related genes implicated in SCZ. AIM The aim of this study is to identify genetic and epigenetic changes that have been reported in glial cells or glial-associated genes in SCZ. MATERIALS AND METHODS We searched the articles from PubMed, PubMed Central, Medline, Medscape, and Embase databases up to December 2020 to identify relevant peer-reviewed articles in English. The titles and abstracts were screened to eliminate irrelevant citations. RESULTS Twenty-four original articles were included in the review. Studies were categorized into the following four thematic via: (1) oligodendrocytes, (2) microglia, (3) astrocytes, and (4) perspectives. CONCLUSION This study is the first of its kind to review research on genetic variants and epigenetic modifications associated with glia-related genes implicated in SCZ. Epigenetic evidence is considerably less than genetic evidence in this field. Understanding the pathways of some risk genes and their genetic and epigenetic regulation allows us to understand and find potential targets for future interventions in this mental illness.
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Affiliation(s)
- Ramos Daniel Francisco
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
| | - Vazquez Fernando
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico.,Research Unit, General Hospital 450, Durango, Mexico
| | - Estrada Norma
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
| | - Méndez Edna Madai
- Scientific Research Institute, Juarez University of the State of Durango, Durango, Mexico
| | - Barraza Marcelo
- Faculty of Chemical Sciences, Juarez University of the State of Durango, Durango, Mexico
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Role of Receptors in Relation to Plaques and Tangles in Alzheimer's Disease Pathology. Int J Mol Sci 2021; 22:ijms222312987. [PMID: 34884789 PMCID: PMC8657621 DOI: 10.3390/ijms222312987] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Revised: 11/26/2021] [Accepted: 11/28/2021] [Indexed: 12/23/2022] Open
Abstract
Despite the identification of Aβ plaques and NFTs as biomarkers for Alzheimer’s disease (AD) pathology, therapeutic interventions remain elusive, with neither an absolute prophylactic nor a curative medication available to impede the progression of AD presently available. Current approaches focus on symptomatic treatments to maintain AD patients’ mental stability and behavioral symptoms by decreasing neuronal degeneration; however, the complexity of AD pathology requires a wide range of therapeutic approaches for both preventive and curative treatments. In this regard, this review summarizes the role of receptors as a potential target for treating AD and focuses on the path of major receptors which are responsible for AD progression. This review gives an overall idea centering on major receptors, their agonist and antagonist and future prospects of viral mimicry in AD pathology. This article aims to provide researchers and developers a comprehensive idea about the different receptors involved in AD pathogenesis that may lead to finding a new therapeutic strategy to treat AD.
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The pivotal role of the NLRC4 inflammasome in neuroinflammation after intracerebral hemorrhage in rats. Exp Mol Med 2021; 53:1807-1818. [PMID: 34848837 PMCID: PMC8639719 DOI: 10.1038/s12276-021-00702-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/24/2021] [Accepted: 09/28/2021] [Indexed: 11/30/2022] Open
Abstract
The NLRC4 inflammasome, a member of the nucleotide-binding and oligomerization domain-like receptor (NLR) family, amplifies inflammation by facilitating the processing of caspase-1, interleukin (IL)-1β, and IL-18. We explored whether NLRC4 knockdown alleviated inflammatory injury following intracerebral hemorrhage (ICH). Furthermore, we investigated whether NLRC4 inflammasome activation can be adjusted by the regulator of G protein signaling 2/leucine-rich repeat kinase-2 pathway. Fifty microliters of arterial blood was drawn and injected into the basal ganglion to simulate the ICH model. NLRC4 small interfering RNAs (siRNAs) were utilized to knockdown NLRC4. An LRRK2 inhibitor (GNE7915) was injected into the abdominal cavity. Short hairpin (sh) RNA lentiviruses and lentiviruses containing RGS2 were designed and applied to knockdown and promote RGS2 expression. Neurological functions, brain edema, Western blot, enzyme-linked immunosorbent, hematoxylin and eosin staining, Nissl staining, immunoprecipitation, immunofluorescence assay and Evans blue dye extravasation and autofluorescence assay were evaluated. It was shown that the NLRC4 inflammasome was activated following ICH injury. NLRC4 knockdown extenuated neuronal death, damage to the blood-brain barrier, brain edema and neurological deficiency 3 days after ICH. NLRC4 knockdown reduced myeloperoxidase (MPO) cells as well as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β and IL-18 following ICH. GNE7915 reduced pNLRC4 and NLRC4 inflammasome activation. RGS2 suppressed the interaction of LRRK2 and NLRC4 and NLRC4 inflammasome activation by regulating pLRRK2. Our study demonstrated that the NLRC4 inflammasome may aggravate the inflammatory injury induced by ICH and that RGS2/LRRK2 may relieve inflammatory injury by restraining NLRC4 inflammasome activation.
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Parmar S, Tadavarty R, Sastry BR. G-protein coupled receptors and synaptic plasticity in sleep deprivation. World J Psychiatry 2021; 11:954-980. [PMID: 34888167 PMCID: PMC8613756 DOI: 10.5498/wjp.v11.i11.954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 06/05/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
Insufficient sleep has been correlated to many physiological and psychoneurological disorders. Over the years, our understanding of the state of sleep has transcended from an inactive period of rest to a more active state involving important cellular and molecular processes. In addition, during sleep, electrophysiological changes also occur in pathways in specific regions of the mammalian central nervous system (CNS). Activity mediated synaptic plasticity in the CNS can lead to long-term and sometimes permanent strengthening and/or weakening synaptic strength affecting neuronal network behaviour. Memory consolidation and learning that take place during sleep cycles, can be affected by changes in synaptic plasticity during sleep disturbances. G-protein coupled receptors (GPCRs), with their versatile structural and functional attributes, can regulate synaptic plasticity in CNS and hence, may be potentially affected in sleep deprived conditions. In this review, we aim to discuss important functional changes that can take place in the CNS during sleep and sleep deprivation and how changes in GPCRs can lead to potential problems with therapeutics with pharmacological interventions.
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Affiliation(s)
- Shweta Parmar
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Ramakrishna Tadavarty
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
| | - Bhagavatula R Sastry
- Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver V6T 1Z3, British Columbia, Canada
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Mirabella F, Desiato G, Mancinelli S, Fossati G, Rasile M, Morini R, Markicevic M, Grimm C, Amegandjin C, Termanini A, Peano C, Kunderfranco P, di Cristo G, Zerbi V, Menna E, Lodato S, Matteoli M, Pozzi D. Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring. Immunity 2021; 54:2611-2631.e8. [PMID: 34758338 PMCID: PMC8585508 DOI: 10.1016/j.immuni.2021.10.006] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/24/2021] [Accepted: 10/07/2021] [Indexed: 02/07/2023]
Abstract
Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.
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Affiliation(s)
- Filippo Mirabella
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Genni Desiato
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council, 20139 Milan, Italy
| | - Sara Mancinelli
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Giuliana Fossati
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Marco Rasile
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy
| | - Raffaella Morini
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Marija Markicevic
- Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland
| | - Christina Grimm
- Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland
| | - Clara Amegandjin
- Department of Neurosciences, Université de Montréal, Montréal, QC, Canada; CHU Sainte-Justine Research Center, Montréal, QC, Canada
| | - Alberto Termanini
- Bioinformatic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy
| | - Clelia Peano
- Institute of Genetic and Biomedical Research, UoS Milan, National Research Council, 20089 Rozzano, Milan, Italy; Genomic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy
| | - Paolo Kunderfranco
- Bioinformatic Unit, Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy
| | - Graziella di Cristo
- Department of Neurosciences, Université de Montréal, Montréal, QC, Canada; CHU Sainte-Justine Research Center, Montréal, QC, Canada
| | - Valerio Zerbi
- Neuroscience Center Zürich, ETH Zürich and University of Zürich, Zürich 8057, Switzerland; Neural Control of Movement Lab, Department of Health Sciences and Technology, ETH Zürich, Zürich 8057, Switzerland
| | - Elisabetta Menna
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council, 20139 Milan, Italy
| | - Simona Lodato
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Michela Matteoli
- IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy; Institute of Neuroscience - National Research Council, 20139 Milan, Italy.
| | - Davide Pozzi
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, via Manzoni 56, 20089 Rozzano, Milan, Italy.
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Milanesi E, Cucos CA, Matias-Guiu JA, Piñol-Ripoll G, Manda G, Dobre M, Cuadrado A. Reduced Blood RGS2 Expression in Mild Cognitive Impairment Patients. Front Aging Neurosci 2021; 13:738244. [PMID: 34658840 PMCID: PMC8513788 DOI: 10.3389/fnagi.2021.738244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/08/2021] [Indexed: 11/30/2022] Open
Abstract
Regulator of G protein signaling 2 (RGS2) is a gene involved in neuronal plasticity and synaptic signaling, whose expression in the brain is altered in neuropsychiatric and neurodegenerative disorders. Microarray data from large datasets suggested reduced RGS2 mRNA levels in the post-mortem brain tissue and blood of Alzheimer’s disease (AD) patients. The results were previously confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) only ex vivo in lymphoblastoid cell lines derived from AD patients and controls. In this study, we compared RGS2 mRNA levels in peripheral blood samples from 69 mild cognitive impairment (MCI) patients to 50 age- and sex-matched non-cognitively impaired controls, out of which 25 patients were monitored at 1 year. We found that RGS2 was indeed downregulated in the peripheral blood of these patients (FR = −1.60, p < 0.001), and despite disease-specific therapy, RGS2 transcript levels continued to decrease at 1 year. The results suggest that RGS2 seems to be involved in AD pathology and progression and can be introduced in a panel of blood AD biomarkers.
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Affiliation(s)
- Elena Milanesi
- "Victor Babes" National Institute of Pathology, Bucharest, Romania
| | | | - Jordi A Matias-Guiu
- Department of Neurology, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain
| | - Gerard Piñol-Ripoll
- Unitat Trastons Cognitius, Hospital Universitari Santa Maria-IRBL Leida, Lleida, Spain
| | - Gina Manda
- "Victor Babes" National Institute of Pathology, Bucharest, Romania
| | - Maria Dobre
- "Victor Babes" National Institute of Pathology, Bucharest, Romania
| | - Antonio Cuadrado
- "Victor Babes" National Institute of Pathology, Bucharest, Romania.,Department of Endocrine Physiology and Nervous System, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC, Madrid, Spain.,Faculty of Medicine, Department of Biochemistry, Autonomous University of Madrid, Madrid, Spain.,Neuroscience Section, Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain
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42
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Proteomic Analysis Unveils Expressional Changes in Cytoskeleton- and Synaptic Plasticity-Associated Proteins in Rat Brain Six Months after Withdrawal from Morphine. Life (Basel) 2021; 11:life11070683. [PMID: 34357055 PMCID: PMC8304287 DOI: 10.3390/life11070683] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/28/2021] [Accepted: 07/10/2021] [Indexed: 11/17/2022] Open
Abstract
Drug withdrawal is associated with abstinence symptoms including deficits in cognitive functions that may persist even after prolonged discontinuation of drug intake. Cognitive deficits are, at least partially, caused by alterations in synaptic plasticity but the precise molecular mechanisms have not yet been fully identified. In the present study, changes in proteomic and phosphoproteomic profiles of selected brain regions (cortex, hippocampus, striatum, and cerebellum) from rats abstaining for six months after cessation of chronic treatment with morphine were determined by label-free quantitative (LFQ) proteomic analysis. Interestingly, prolonged morphine withdrawal was found to be associated especially with alterations in protein phosphorylation and to a lesser extent in protein expression. Gene ontology (GO) term analysis revealed enrichment in biological processes related to synaptic plasticity, cytoskeleton organization, and GTPase activity. More specifically, significant changes were observed in proteins localized in synaptic vesicles (e.g., synapsin-1, SV2a, Rab3a), in the active zone of the presynaptic nerve terminal (e.g., Bassoon, Piccolo, Rims1), and in the postsynaptic density (e.g., cadherin 13, catenins, Arhgap35, Shank3, Arhgef7). Other differentially phosphorylated proteins were associated with microtubule dynamics (microtubule-associated proteins, Tppp, collapsin response mediator proteins) and the actin–spectrin network (e.g., spectrins, adducins, band 4.1-like protein 1). Taken together, a six-month morphine withdrawal was manifested by significant alterations in the phosphorylation of synaptic proteins. The altered phosphorylation patterns modulating the function of synaptic proteins may contribute to long-term neuroadaptations induced by drug use and withdrawal.
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Jeon JH, Oh TR, Park S, Huh S, Kim JH, Mai BK, Lee JH, Kim SH, Lee MJ. The Antipsychotic Drug Clozapine Suppresses the RGS4 Polyubiquitylation and Proteasomal Degradation Mediated by the Arg/N-Degron Pathway. Neurotherapeutics 2021; 18:1768-1782. [PMID: 33884581 PMCID: PMC8608952 DOI: 10.1007/s13311-021-01039-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2021] [Indexed: 02/04/2023] Open
Abstract
Although diverse antipsychotic drugs have been developed for the treatment of schizophrenia, most of their mechanisms of action remain elusive. Regulator of G-protein signaling 4 (RGS4) has been reported to be linked, both genetically and functionally, with schizophrenia and is a physiological substrate of the arginylation branch of the N-degron pathway (Arg/N-degron pathway). Here, we show that the atypical antipsychotic drug clozapine significantly inhibits proteasomal degradation of RGS4 proteins without affecting their transcriptional expression. In addition, the levels of Arg- and Phe-GFP (artificial substrates of the Arg/N-degron pathway) were significantly elevated by clozapine treatment. In silico computational model suggested that clozapine may interact with active sites of N-recognin E3 ubiquitin ligases. Accordingly, treatment with clozapine resulted in reduced polyubiquitylation of RGS4 and Arg-GFP in the test tube and in cultured cells. Clozapine attenuated the activation of downstream effectors of G protein-coupled receptor signaling, such as MEK1 and ERK1, in HEK293 and SH-SY5Y cells. Furthermore, intraperitoneal injection of clozapine into rats significantly stabilized the endogenous RGS4 protein in the prefrontal cortex. Overall, these results reveal an additional therapeutic mechanism of action of clozapine: this drug posttranslationally inhibits the degradation of Arg/N-degron substrates, including RGS4. These findings imply that modulation of protein post-translational modifications, in particular the Arg/N-degron pathway, may be a novel molecular therapeutic strategy against schizophrenia.
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Affiliation(s)
- Jun Hyoung Jeon
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Tae Rim Oh
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Seoyoung Park
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Sunghoo Huh
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Korea
| | - Ji Hyeon Kim
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Binh Khanh Mai
- Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Jung Hoon Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea
| | - Se Hyun Kim
- Biomedical Research Institute, Seoul National University Hospital, Seoul, 03080, Korea.
- Department of Psychiatry, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, 03080, Korea.
| | - Min Jae Lee
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 03080, Korea.
- Neuroscience Research Institute, Seoul National University College of Medicine, Seoul, 03080, Korea.
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RGS14 Regulation of Post-Synaptic Signaling and Spine Plasticity in Brain. Int J Mol Sci 2021; 22:ijms22136823. [PMID: 34201943 PMCID: PMC8268017 DOI: 10.3390/ijms22136823] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 06/12/2021] [Accepted: 06/14/2021] [Indexed: 02/06/2023] Open
Abstract
The regulator of G-protein signaling 14 (RGS14) is a multifunctional signaling protein that regulates post synaptic plasticity in neurons. RGS14 is expressed in the brain regions essential for learning, memory, emotion, and stimulus-induced behaviors, including the basal ganglia, limbic system, and cortex. Behaviorally, RGS14 regulates spatial and object memory, female-specific responses to cued fear conditioning, and environmental- and psychostimulant-induced locomotion. At the cellular level, RGS14 acts as a scaffolding protein that integrates G protein, Ras/ERK, and calcium/calmodulin signaling pathways essential for spine plasticity and cell signaling, allowing RGS14 to naturally suppress long-term potentiation (LTP) and structural plasticity in hippocampal area CA2 pyramidal cells. Recent proteomics findings indicate that RGS14 also engages the actomyosin system in the brain, perhaps to impact spine morphogenesis. Of note, RGS14 is also a nucleocytoplasmic shuttling protein, where its role in the nucleus remains uncertain. Balanced nuclear import/export and dendritic spine localization are likely essential for RGS14 neuronal functions as a regulator of synaptic plasticity. Supporting this idea, human genetic variants disrupting RGS14 localization also disrupt RGS14’s effects on plasticity. This review will focus on the known and unexplored roles of RGS14 in cell signaling, physiology, disease and behavior.
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45
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Ferkey DM, Sengupta P, L’Etoile ND. Chemosensory signal transduction in Caenorhabditis elegans. Genetics 2021; 217:iyab004. [PMID: 33693646 PMCID: PMC8045692 DOI: 10.1093/genetics/iyab004] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/05/2021] [Indexed: 12/16/2022] Open
Abstract
Chemosensory neurons translate perception of external chemical cues, including odorants, tastants, and pheromones, into information that drives attraction or avoidance motor programs. In the laboratory, robust behavioral assays, coupled with powerful genetic, molecular and optical tools, have made Caenorhabditis elegans an ideal experimental system in which to dissect the contributions of individual genes and neurons to ethologically relevant chemosensory behaviors. Here, we review current knowledge of the neurons, signal transduction molecules and regulatory mechanisms that underlie the response of C. elegans to chemicals, including pheromones. The majority of identified molecules and pathways share remarkable homology with sensory mechanisms in other organisms. With the development of new tools and technologies, we anticipate that continued study of chemosensory signal transduction and processing in C. elegans will yield additional new insights into the mechanisms by which this animal is able to detect and discriminate among thousands of chemical cues with a limited sensory neuron repertoire.
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Affiliation(s)
- Denise M Ferkey
- Department of Biological Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14260, USA
| | - Piali Sengupta
- Department of Biology, Brandeis University, Waltham, MA 02454, USA
| | - Noelle D L’Etoile
- Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143, USA
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Kiel C, Matallanas D, Kolch W. The Ins and Outs of RAS Effector Complexes. Biomolecules 2021; 11:236. [PMID: 33562401 PMCID: PMC7915224 DOI: 10.3390/biom11020236] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 01/31/2021] [Accepted: 02/03/2021] [Indexed: 12/12/2022] Open
Abstract
RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.
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Affiliation(s)
- Christina Kiel
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; (C.K.); (D.M.)
- UCD Charles Institute of Dermatology, School of Medicine, University College Dublin, Dublin 4, Ireland
| | - David Matallanas
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; (C.K.); (D.M.)
| | - Walter Kolch
- Systems Biology Ireland, School of Medicine, University College Dublin, Dublin 4, Ireland; (C.K.); (D.M.)
- Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Dublin 4, Ireland
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Galet B, Ingallinesi M, Pegon J, Do Thi A, Ravassard P, Faucon Biguet N, Meloni R. G-protein coupled receptor 88 knockdown in the associative striatum reduces psychiatric symptoms in a translational male rat model of Parkinson disease. J Psychiatry Neurosci 2021; 46:E44-E55. [PMID: 32667145 PMCID: PMC7955842 DOI: 10.1503/jpn.190171] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In addition to motor disability, another characteristic feature of Parkinson disease is the early appearance of psychiatric symptoms, including apathy, depression, anxiety and cognitive deficits; treatments for these symptoms are limited by the development of adverse effects such as impulse-control disorders. In this context, we investigated the orphan G protein-coupled receptor 88 (GPR88) as a novel therapeutic target. METHODS We used lentiviral-mediated expression of specifically designed microRNA to knock down Gpr88 in a translational male rat model of early Parkinson disease obtained by dopamine loss in the dorsolateral striatum as a result of 6-hydroxydopamine lesions. We evaluated the impact of Gpr88 knockdown on the Parkinson disease model using behavioural, immunohistochemical and in situ hybridization studies. RESULTS Knockdown of Gpr88 in associative territories of the dorsal striatum efficiently reduced alterations in mood, motivation and cognition through modulation of the regulator of the G-protein signalling 4 and of the truncated splice variant of the FosB transcription factor. Knockdown of Gpr88 also reduced allostatic changes in striatal activity markers that may be related to patterns observed in patients and that provide support for an "overload" hypothesis for the etiology of the psychiatric symptoms of Parkinson disease. LIMITATIONS Behavioural tests assessing specific cognitive and motivational parameters are needed to further characterize the effects of the lesion and of Gpr88 knockdown in early-stage and advanced Parkinson disease models, presenting more extensive dopamine loss. Additional studies focusing on the direct and indirect striatal output pathways are also required, because little is known about the signalling pathways regulated by GPR88 in different striatal cell types. CONCLUSION GPR88 may constitute a highly relevant target for the treatment of the psychiatric symptoms of Parkinson disease.
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Affiliation(s)
- Benjamin Galet
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Manuela Ingallinesi
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Jonathan Pegon
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Anh Do Thi
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Philippe Ravassard
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Nicole Faucon Biguet
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
| | - Rolando Meloni
- Biotechnology and Biotherapy team, ICM Brain and Spine Institute, Sorbonne University/INSERM U 1127/CNRS UMR 7225, CHU Pitié-Salpêtrière, Paris, France (Galet, Ingallinesi, Pegon, Do Thi, Ravassard, Faucon Biguet, Meloni)
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48
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Squires KE, Gerber KJ, Tillman MC, Lustberg DJ, Montañez-Miranda C, Zhao M, Ramineni S, Scharer CD, Saha RN, Shu FJ, Schroeder JP, Ortlund EA, Weinshenker D, Dudek SM, Hepler JR. Human genetic variants disrupt RGS14 nuclear shuttling and regulation of LTP in hippocampal neurons. J Biol Chem 2021; 296:100024. [PMID: 33410399 PMCID: PMC7949046 DOI: 10.1074/jbc.ra120.016009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/26/2020] [Accepted: 11/04/2020] [Indexed: 12/13/2022] Open
Abstract
The human genome contains vast genetic diversity as naturally occurring coding variants, yet the impact of these variants on protein function and physiology is poorly understood. RGS14 is a multifunctional signaling protein that suppresses synaptic plasticity in dendritic spines of hippocampal neurons. RGS14 also is a nucleocytoplasmic shuttling protein, suggesting that balanced nuclear import/export and dendritic spine localization are essential for RGS14 functions. We identified genetic variants L505R (LR) and R507Q (RQ) located within the nuclear export sequence (NES) of human RGS14. Here we report that RGS14 encoding LR or RQ profoundly impacts protein functions in hippocampal neurons. RGS14 membrane localization is regulated by binding Gαi-GDP, whereas RGS14 nuclear export is regulated by Exportin 1 (XPO1). Remarkably, LR and RQ variants disrupt RGS14 binding to Gαi1-GDP and XPO1, nucleocytoplasmic equilibrium, and capacity to inhibit long-term potentiation (LTP). Variant LR accumulates irreversibly in the nucleus, preventing RGS14 binding to Gαi1, localization to dendritic spines, and inhibitory actions on LTP induction, while variant RQ exhibits a mixed phenotype. When introduced into mice by CRISPR/Cas9, RGS14-LR protein expression was detected predominantly in the nuclei of neurons within hippocampus, central amygdala, piriform cortex, and striatum, brain regions associated with learning and synaptic plasticity. Whereas mice completely lacking RGS14 exhibit enhanced spatial learning, mice carrying variant LR exhibit normal spatial learning, suggesting that RGS14 may have distinct functions in the nucleus independent from those in dendrites and spines. These findings show that naturally occurring genetic variants can profoundly alter normal protein function, impacting physiology in unexpected ways.
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Affiliation(s)
- Katherine E Squires
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta Georgia, USA
| | - Kyle J Gerber
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta Georgia, USA
| | | | - Daniel J Lustberg
- Department of Human Genetics, Emory University, Atlanta Georgia, USA
| | | | - Meilan Zhao
- National Institute of Environmental Health Sciences, Research Triangle Park, Raleigh North Carolina, USA
| | - Suneela Ramineni
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta Georgia, USA
| | | | - Ramendra N Saha
- Department of Molecular & Cell Biology, University of California-Merced, Merced California, USA
| | - Feng-Jue Shu
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta Georgia, USA
| | - Jason P Schroeder
- Department of Human Genetics, Emory University, Atlanta Georgia, USA
| | - Eric A Ortlund
- Department of Biochemistry, Emory University, Atlanta Georgia, USA
| | - David Weinshenker
- Department of Human Genetics, Emory University, Atlanta Georgia, USA
| | - Serena M Dudek
- National Institute of Environmental Health Sciences, Research Triangle Park, Raleigh North Carolina, USA
| | - John R Hepler
- Department of Pharmacology and Chemical Biology, Emory University, Atlanta Georgia, USA.
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49
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Piras IS, Krate J, Delvaux E, Nolz J, Mastroeni DF, Persico AM, Jepsen WM, Beach TG, Huentelman MJ, Coleman PD. Transcriptome Changes in the Alzheimer's Disease Middle Temporal Gyrus: Importance of RNA Metabolism and Mitochondria-Associated Membrane Genes. J Alzheimers Dis 2020; 70:691-713. [PMID: 31256118 DOI: 10.3233/jad-181113] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.
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Affiliation(s)
- Ignazio S Piras
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Jonida Krate
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Elaine Delvaux
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Jennifer Nolz
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Diego F Mastroeni
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
| | - Antonio M Persico
- Unit of Child and Adolescent Neuropsychiatry, "Gaetano Martino" University Hospital, University of Messina, Messina, Italy.,Mafalda Luce Center for Pervasive Developmental Disorders, Milan, Italy
| | - Wayne M Jepsen
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Thomas G Beach
- Civin Laboratory of Neuropathology at Banner Sun Health Research Institute, Sun City, AZ, US
| | - Matthew J Huentelman
- Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ, USA
| | - Paul D Coleman
- Biodesign Institute, Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ, USA
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Mechanisms and Regulation of Neuronal GABA B Receptor-Dependent Signaling. Curr Top Behav Neurosci 2020; 52:39-79. [PMID: 32808092 DOI: 10.1007/7854_2020_129] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
γ-Aminobutyric acid B receptors (GABABRs) are broadly expressed throughout the central nervous system where they play an important role in regulating neuronal excitability and synaptic transmission. GABABRs are G protein-coupled receptors that mediate slow and sustained inhibitory actions via modulation of several downstream effector enzymes and ion channels. GABABRs are obligate heterodimers that associate with diverse arrays of proteins to form modular complexes that carry out distinct physiological functions. GABABR-dependent signaling is fine-tuned and regulated through a multitude of mechanisms that are relevant to physiological and pathophysiological states. This review summarizes the current knowledge on GABABR signal transduction and discusses key factors that influence the strength and sensitivity of GABABR-dependent signaling in neurons.
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