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Dhureja M, Munshi A, Kumar P. AMPK as a Therapeutic Target: Advancing Epilepsy Management Through Metabolic Modulation. Mol Neurobiol 2025; 62:7820-7834. [PMID: 39937419 DOI: 10.1007/s12035-025-04745-4] [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: 10/04/2024] [Accepted: 02/04/2025] [Indexed: 02/13/2025]
Abstract
Epilepsy is often marked by paroxysmal seizures that disrupt the brain's sensory, motor, and psychosocial functions. The underlying pathology is generally believed to involve an imbalance between excitatory and inhibitory neurotransmission. However, a less explored but significant contributor to epilepsy is the collapse of the brain's metabolic and bioenergetic systems. The breakdown of the brain's bioenergetic system leads to the activation of various detrimental downstream signaling cascades that ultimately result in oxidative stress, neuroinflammation, and reduced autophagic flux, all of which impair neuronal-glial communication and precipitate epileptic attacks. This highlights the pressing need for a therapeutic agent to address these complex challenges. Researchers have identified adenosine monophosphate kinase (AMPK) as a potential solution. AMPK acts as the body's primary stress sensor, activated in response to the deficiency of growth factors and nutrient starvation to restore energy homeostasis. AMPK activation also maintains the intricate communication between neurons and glial cells, preserving synaptic plasticity integrity, mitigating mitochondrial damage, and dampening inflammatory signaling cascades. Despite demonstrating significant efficacy in managing a range of peripheral and neurological disorders, the role of AMPK in neurotransmission and epilepsy remains unexplored. This review explores the multifaceted molecular roles of AMPK beyond its traditional metabolic regulatory functions, suggesting that targeting AMPK could provide a novel avenue for drug development in epilepsy treatment.
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Affiliation(s)
- Maanvi Dhureja
- Department of Pharmacology, Central University of Punjab, Bathinda, India
| | - Anjana Munshi
- Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Bathinda, India.
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Xie W, Li Y, Wang X, Blokhina E, Krupitsky E, Vetrova M, Hu J, Yuan T, Chen J, Wang H, Chen X. GABA B Receptor: Structure, Biological Functions, and Therapy for Diseases. MedComm (Beijing) 2025; 6:e70163. [PMID: 40242161 PMCID: PMC12000685 DOI: 10.1002/mco2.70163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 12/29/2024] [Accepted: 02/19/2025] [Indexed: 04/18/2025] Open
Abstract
Gamma-aminobutyric acid (GABA) B receptors (GABABRs) that acts slowly and maintains the inhibitory tone are versatile regulators in the complex nervous behaviors and their involvement in various neuropsychiatric disorders, such as anxiety, epilepsy, pain, drug addiction, and Alzheimer's disease. Additional study advances have implied the crucial roles of GABABRs in regulating feeding-related behaviors, yet their therapeutic potential in addressing the neuropsychiatric disorders, binge eating, and feeding-related disorders remains underutilized. This general review summarized the physiological structure and functions of GABABR, explored the regulation in various psychiatric disorders, feeding behaviors, binge eating, and metabolism disorders, and fully discussed the potential of targeting GABABRs and its regulator-binding sites for the treatment of different psychiatric disorders, binge eating and even obesity. While agonists that directly bind to GABABR1 have some negative side effects, positive allosteric modulators (PAMs) that bind to GABABR2 demonstrate excellent therapeutic efficacy and tolerability and have better safety and therapeutic indexes. Moreover, phosphorylation sites of downstream GABABRs regulators may be novel therapeutic targets for psychiatric disorders, binge eating, and obesity. Further studies, clinical trials in particular, will be essential for confirming the therapeutic value of PAMs and other agents targeting the GABABR pathways in a clinical setting.
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Affiliation(s)
- Weijie Xie
- Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health CenterTongji University School of MedicineShanghaiChina
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghaiChina
| | - Yuan Li
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghaiChina
| | - Xinyue Wang
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghaiChina
| | - Elena Blokhina
- Valdman Institute of PharmacologyPavlov UniversitySt. PetersburgRussia
| | - Evgeny Krupitsky
- Valdman Institute of PharmacologyPavlov UniversitySt. PetersburgRussia
- Bekhterev National Medical Research Center for Psychiatry and NeurologySt. PetersburgRussia
| | - Marina Vetrova
- Valdman Institute of PharmacologyPavlov UniversitySt. PetersburgRussia
| | - Ji Hu
- ShanghaiTech UniversityShanghaiChina
| | - Ti‐Fei Yuan
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghaiChina
- Co‐innovation Center of NeuroregenerationNantong UniversityNantongJiangsuChina
| | - Jue Chen
- Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health CenterShanghai Jiaotong University School of MedicineShanghaiChina
| | - Hua Wang
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
| | - Xiangfang Chen
- Department of EndocrinologySecond Affiliated Hospital of Naval Medical UniversityShanghaiChina
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Chen IC, Pai YW, Lin JF, Chen YM, Lin KC, Chen HH, Lin CH. Association of antidiabetic medications with depression risk and All-Cause mortality in type 2 Diabetes: A TriNetX-Based cohort study. Diabetes Res Clin Pract 2025; 223:112167. [PMID: 40204122 DOI: 10.1016/j.diabres.2025.112167] [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: 12/02/2024] [Revised: 03/30/2025] [Accepted: 04/06/2025] [Indexed: 04/11/2025]
Abstract
AIMS Individuals with type 2 diabetes face elevated risks of depression and all-cause mortality. This study aimed to compare the associations of different glucose-lowering drugs-metformin, GLP-1 receptor agonists (GLP-1 RA), DPP-4 inhibitors (DPP-4i), and SGLT-2 inhibitors (SGLT-2i)-with these risks. METHODS Using TriNetX, we conducted a retrospective cohort study of 359,787 patients with type 2 diabetes receiving monotherapy with the aforementioned drugs. Propensity score matching balanced baseline characteristics, and Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident depression and all-cause mortality. Additional subgroup analyses were performed stratified by sex and age. RESULTS We assessed the association between glucose-lowering therapies and the risk of depression and all-cause mortality over 1-, 3-, and 5-year follow-up periods. Compared to metformin, GLP-1 RA users were associated with a higher risk of depression (HR 1.54-1.84) and a modestly elevated risk of all-cause mortality at 1 and 3 years (HR 1.19 and 1.21, respectively), though this association was not observed at 5 years. Relative to SGLT-2 inhibitors (SGLT-2i), GLP-1 RA users demonstrated a higher risk of depression (HR 1.33-1.59) and all-cause mortality (HR 1.24-1.35). SGLT-2i use was associated with a lower risk of depression (HR 0.62-0.70) and all-cause mortality (HR 0.54-0.65) compared to DPP-4 inhibitors (DPP-4i). Notably, DPP-4i users exhibited the highest risk of both depression and all-cause mortality relative to metformin (HR 1.53-1.74 and HR 1.56-1.57, respectively). CONCLUSION SGLT-2i was associated with significant reductions in depression and mortality risks, highlighting its potential advantages for type 2 diabetes management. 1 Background.
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Affiliation(s)
- I-Chieh Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yen-Wei Pai
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; Department of Neurology, Neurological Institute, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jun-Fu Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Yi-Ming Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Science and Rong-Hsing Research Center for Translational Medicine, Chung-Hsing University, Taichung, Taiwan; School of Medicine, National Yang-Ming Chiao Tung University, Taipei, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung, Taiwan; Precision Medicine Research Center, College of Medicine, National Chung-Hsing University, Taichung, Taiwan
| | - Kuan-Chia Lin
- Cheng Hsin General Hospital, Taipei, Taiwan; Institute of Hospital and Health Care Administration National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsin-Hua Chen
- Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan; Institute of Biomedical Science and Rong-Hsing Research Center for Translational Medicine, Chung-Hsing University, Taichung, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung-Hsing University, Taichung, Taiwan
| | - Ching-Heng Lin
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan; Department of Public Health, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan; Department of Industrial Engineering and Enterprise Information, Tunghai University, Taichung, Taiwan; Institute of Public Health and Community Medicine Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan; Department of Epidemiology and Public Health, UCL, London, United Kingdom.
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Hleihil M, Bhat MA, Grampp T, Benke D. Optimization of neuron-specific interfering peptides targeting GABA B receptor downregulation for proteolytic stability for conferring neuroprotection in a mouse model of cerebral ischemia. Front Pharmacol 2025; 16:1576884. [PMID: 40356975 PMCID: PMC12066480 DOI: 10.3389/fphar.2025.1576884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 04/09/2025] [Indexed: 05/15/2025] Open
Abstract
Background Cerebral ischemia triggers a cascade of detrimental events, leading to brain damage mainly due to the over-excitation of neurons. Currently, clinically applicable neuroprotective treatments to stop progressive neuronal death remain elusive. The GABAB receptor, crucial for neuronal inhibition, is a promising target for neuroprotection because it inhibits neuronal over-excitation which otherwise leads to excitotoxic death. However, ischemic conditions impair GABAB receptor function by downregulating the receptors via pathologically altered trafficking events. Previously, we developed interfering peptides to inhibit the interaction of GABAB receptors with key interacting proteins, leading to the pathological downregulation of the receptors. These interfering peptides restored GABAB receptor expression and function, resulting in reduced excitability and death of neurons in in-vitro and ex-vivo models of cerebral ischemia. However, the interfering peptides were not effective in-vivo because of their limited proteolytic stability after systemic application. Methods/results Here, we aimed to render three interfering peptides resistant to proteolytic degradation by replacing natural L-amino acids by D-amino acids. Additionally, we optimized a blood brain barrier shuttle (BBBpS) sequence derived from the Rabies virus glycoprotein (RVG) that mediates neuron-specific uptake and blood-brain barrier crossing of these interfering peptides. By optimizing the peptides, we developed stable, neuron-specific interfering peptides that successfully restored GABAB receptors expression and prevented neuronal death following excitotoxic stress in cultured neurons. In vivo testing in the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia demonstrated the neuroprotective activity of the optimized peptides by a significantly reduced infarct size. Conclusion These findings confirm the potential of these peptides as neuroprotective agents and emphasize the importance of proteolytic stability of peptide drugs for their successful in-vivo application.
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Affiliation(s)
- Mohammad Hleihil
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Musadiq A. Bhat
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Thomas Grampp
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Dietmar Benke
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University and ETH Zurich, Zurich, Switzerland
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Yamagishi A, Yonemochi N, Kimura A, Takenoya F, Shioda S, Waddington JL, Ikeda H. AMP-activated protein kinase in the amygdala and hippocampus contributes to enhanced fear memory in diabetic mice. Br J Pharmacol 2024; 181:5028-5040. [PMID: 39295124 DOI: 10.1111/bph.17338] [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: 04/02/2024] [Revised: 07/01/2024] [Accepted: 07/23/2024] [Indexed: 09/21/2024] Open
Abstract
BACKGROUND AND PURPOSE Diabetic patients have an increased risk of psychiatric disorders. Because hyperglycaemia increases L-lactate in the brain and L-lactate inhibits AMP-activated protein kinase (AMPK), this study investigated the role of L-lactate and AMPK in strengthened fear memory, a model for human psychiatric disorders, in diabetic mice. EXPERIMENTAL APPROACH The diabetic model was mice injected with streptozotocin. Fear memory was measured using the conditioned fear test with low (0.45 mA) or high (0.50 mA) foot shock to cause low and high freezing, respectively. Protein levels of AMPK and phosphorylated AMPK (pAMPK) were measured by western blotting and immunohistochemistry. KEY RESULTS At 0.45 mA, the AMPK inhibitor dorsomorphin increased freezing, which was inhibited by the AMPK activator acadesine. In contrast, at 0.50 mA, acadesine decreased freezing, which was inhibited by dorsomorphin. In diabetic mice, pAMPK was decreased in the amygdala and hippocampus. Diabetic mice showed increased freezing at 0.45 mA, which was inhibited by acadesine. In the amygdala and hippocampus, L-lactate was increased in diabetic mice and injection of L-lactate into non-diabetic mice increased freezing at 0.45 mA. In addition, L-lactate decreased pAMPK in the hippocampus, but not the amygdala, and increase in freezing induced by L-lactate was inhibited by acadesine. Dorsomorphin-induced increase in freezing was inhibited by the AMPA receptor antagonist NBQX. CONCLUSIONS AND INTERPRETATION In diabetic mice, L-lactate is increased in the amygdala and hippocampus, possibly through hyperglycaemia, which strengthens fear memory through inhibition of AMPK and activation of glutamatergic function.
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Affiliation(s)
- Aimi Yamagishi
- Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Naomi Yonemochi
- Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Ai Kimura
- Global Research Center for Innovative Life Science, Peptide Drug Innovation, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Fumiko Takenoya
- Department of Sport Sciences, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - Seiji Shioda
- Global Research Center for Innovative Life Science, Peptide Drug Innovation, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
| | - John L Waddington
- School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hiroko Ikeda
- Department of Pathophysiology and Therapeutics, Hoshi University School of Pharmacy and Pharmaceutical Sciences, Tokyo, Japan
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Song YT, Li SS, Chao CY, Shuang-Guo, Chen GZ, Wang SX, Zhang MX, Yin YL, Li P. Floralozone regulates MiR-7a-5p expression through AMPKα2 activation to improve cognitive dysfunction in vascular dementia. Exp Neurol 2024; 376:114748. [PMID: 38458310 DOI: 10.1016/j.expneurol.2024.114748] [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: 10/24/2023] [Revised: 02/07/2024] [Accepted: 03/04/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND The pathogenesis of vascular dementia (VD) is complex, and currently, no effective treatments have been recommended. Floralozone is a colorless liquid first discovered in Lagotis Gaertn. Recently, its medicinal value has been increasingly recognized. Our previous study has demonstrated that Floralozone can improve cognitive dysfunction in rats with VD by regulating the transient receptor potential melastatin 2 (TRPM2) and N-methyl-D-aspartate receptor (NMDAR) signaling pathways. However, the mechanism by which Floralozone regulates TRPM2 and NMDAR to improve VD remains unclear. AMP-activated protein kinase (AMPK) is an energy regulator in vivo; however, its role of AMPK activation in stroke remains controversial. MiR-7a-5p has been identified to be closely related to neuronal function. PURPOSE To explore whether Floralozone can regulate the miR-7a-5p level in vivo through AMPKα2 activation, affect the TRPM2 and NR2B expression levels, and improve VD symptoms. METHODS The VD model was established by a modified bilateral occlusion of the common carotid arteries (2-VO) of Sprague-Dawley (SD) rats and AMPKα2 KO transgenic (AMPKα2-/-) mice. Primary hippocampal neurons were modeled using oxygen and glucose deprivation (OGD). Morris water maze (MWM) test, hematoxylin-eosin staining (HE staining), and TUNEL staining were used to investigate the effects of Floralozone on behavior and hippocampal morphology in rats. Minichromosome maintenance complex component 2(MCM2) positive cells were used to investigate the effect of Floralozone on neurogenesis. Immunofluorescence staining, qRT-PCR, and western blot analysis were used to investigate the effect of Floralozone on the expression levels of AMPKα2, miR-7a-5p, TRPM2, and NR2B. RESULTS The SD rat experiment revealed that Floralozone improved spatial learning and memory, improved the morphology and structure of hippocampal neurons, reduced apoptosis of hippocampal neurons and promoted neurogenesis in VD rats. Floralozone could increase the miR-7a-5p expression level, activate AMPKα2 and NR2B expressions, and inhibit TRPM2 expression in hippocampal neurons of VD rats. The AMPKα2 KO transgenic (AMPKα2-/-) mice experiment demonstrated that Floralozone could regulate miR-7a-5p, TRPM2, and NR2B expression levels through AMPKα2 activation. The cell experiment revealed that the TRPM2 and NR2B expression levels were regulated by miR-7a-5p, whereas the AMPKα2 expression level was not. CONCLUSION Floralozone could regulate miR-7a-5p expression level by activating the protein expression of AMPKα2, control the protein expression of TRPM2 and NR2B, improve the morphology and structure of hippocampus neurons, reduce the apoptosis of hippocampus neurons, promote neurogenesis and improve the cognitive dysfunction.
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Affiliation(s)
- Yu-Ting Song
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; JinShan Hospital of Fudan University, Shanghai 201508, China
| | - Shan-Shan Li
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
| | - Chun-Yan Chao
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China; Huang Huai University, Zhumadian 463000, China
| | - Shuang-Guo
- Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, China
| | - Gui-Zi Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shuang-Xi Wang
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
| | - Ming-Xiang Zhang
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China
| | - Ya-Ling Yin
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China.
| | - Peng Li
- Henan international joint laboratory of cardiovascular remodeling and drug intervention, Sino-UK Joint Laboratory of Brain Function and Injury and Department of Physiology and Neurobiology, School of Basic Medical Sciences, College of Pharmacy, Xinxiang Medical University, Xinxiang 453003, China.
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Onishi Y, Yamamura Y, Hosogi M, Higashi H, Ogita K, Kinjo T, Uno K, Yoneda Y, Kuramoto N. Long-lasting increases in GABA B receptor subunit levels in hippocampal dentate gyrus of mice with a single systemic injection of trimethyltin. Heliyon 2024; 10:e29713. [PMID: 38720739 PMCID: PMC11076641 DOI: 10.1016/j.heliyon.2024.e29713] [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: 09/18/2023] [Revised: 03/13/2024] [Accepted: 04/14/2024] [Indexed: 05/12/2024] Open
Abstract
We have recently shown delayed increases in GABAB receptor (GABABR) subunit protein levels in the hippocampal dentate gyrus (DG), but not in the pyramidal CA1 and CA3 regions, at 15-30 days after the systemic single administration of trimethyltin (TMT) in mice. An attempt was thus made to determine whether the delayed increases return to the control levels found in naive mice afterward. In the DG on hippocampal slices obtained at 90 days after the administration, however, marked increases were still seen in protein levels of both GABABR1 and GABABR2 subunits without significant changes in calbindin and glial fibrillary acidic protein (GFAP) levels on immunoblotting analysis. Fluoro-Jade B staining clearly revealed the absence of degenerated neurons from the DG at 90 days after the administration. Although co-localization was invariably detected between GABABR2 subunit and GFAP in the DG at 30 days on immunohistochemical analysis, GABABR2-positive cells did not merge well with GFAP-positive cells in the DG at 90 days. These results suggest that both GABABR1 and GABABR2 subunits would be tardily and sustainably up-regulated by cells other than neurons and astrocytes in the murine DG at 90 days after a systemic single injection of TMT.
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Affiliation(s)
- Yuki Onishi
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
| | - Yusuke Yamamura
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
| | - Misa Hosogi
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
| | - Hiroshi Higashi
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
| | - Kiyokazu Ogita
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
| | - Toshihiko Kinjo
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
| | - Kyosuke Uno
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
| | - Yukio Yoneda
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
| | - Nobuyuki Kuramoto
- Laboratory of Molecular Pharmacology,Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, 140-0001, Tokyo, Japan
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Qi Y, Zhang YM, Gao YN, Chen WG, Zhou T, Chang L, Zang Y, Li J. AMPK role in epilepsy: a promising therapeutic target? J Neurol 2024; 271:748-771. [PMID: 38010498 DOI: 10.1007/s00415-023-12062-w] [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: 07/21/2023] [Revised: 10/11/2023] [Accepted: 10/12/2023] [Indexed: 11/29/2023]
Abstract
Epilepsy is a complex and multifaceted neurological disorder characterized by spontaneous and recurring seizures. It poses significant therapeutic challenges due to its diverse etiology and often-refractory nature. This comprehensive review highlights the pivotal role of AMP-activated protein kinase (AMPK), a key metabolic regulator involved in cellular energy homeostasis, which may be a promising therapeutic target for epilepsy. Current therapeutic strategies such as antiseizure medication (ASMs) can alleviate seizures (up to 70%). However, 30% of epileptic patients may develop refractory epilepsy. Due to the complicated nature of refractory epilepsy, other treatment options such as ketogenic dieting, adjunctive therapy, and in limited cases, surgical interventions are employed. These therapy options are only suitable for a select group of patients and have limitations of their own. Current treatment options for epilepsy need to be improved. Emerging evidence underscores a potential association between impaired AMPK functionality in the brain and the onset of epilepsy, prompting an in-depth examination of AMPK's influence on neural excitability and ion channel regulation, both critical factors implicated in epileptic seizures. AMPK activation through agents such as metformin has shown promising antiepileptic effects in various preclinical and clinical settings. These effects are primarily mediated through the inhibition of the mTOR signaling pathway, activation of the AMPK-PI3K-c-Jun pathway, and stimulation of the PGC-1α pathway. Despite the potential of AMPK-targeted therapies, several aspects warrant further exploration, including the detailed mechanisms of AMPK's role in different brain regions, the impact of AMPK under various conditional circumstances such as neural injury and zinc toxicity, the long-term safety and efficacy of chronic metformin use in epilepsy treatment, and the potential benefits of combination therapy involving AMPK activators. Moreover, the efficacy of AMPK activators in refractory epilepsy remains an open question. This review sets the stage for further research with the aim of enhancing our understanding of the role of AMPK in epilepsy, potentially leading to the development of more effective, AMPK-targeted therapeutic strategies for this challenging and debilitating disorder.
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Affiliation(s)
- Yingbei Qi
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, Zhejiang, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yong-Mei Zhang
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, Zhejiang, China
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Ya-Nan Gao
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- China Pharmaceutical University, Nanjing, 210009, Jiangsu, China
| | - Wen-Gang Chen
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- China Pharmaceutical University, Nanjing, 210009, Jiangsu, China
| | - Ting Zhou
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liuliu Chang
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yi Zang
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Jia Li
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, Zhejiang, China.
- National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Benke D, Bhat MA, Hleihil M. GABAB Receptors: Molecular Organization, Function, and Alternative Drug Development by Targeting Protein-Protein Interactions. THE RECEPTORS 2024:3-39. [DOI: 10.1007/978-3-031-67148-7_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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10
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Kinjo T, Ebisawa S, Nokubo T, Hashimoto M, Yamada T, Oshio M, Nakamura R, Uno K, Kuramoto N. Post-translational modifications of the apelin receptor regulate its functional expression. AIMS Neurosci 2023; 10:282-299. [PMID: 38188005 PMCID: PMC10767067 DOI: 10.3934/neuroscience.2023022] [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: 07/14/2023] [Revised: 10/24/2023] [Accepted: 10/26/2023] [Indexed: 01/09/2024] Open
Abstract
Post-translational modifications (PTMs) are protein modifications that occur after protein biosynthesis, playing a crucial role in regulating protein function. They are involved in the functional expression of G-protein-coupled receptors (GPCRs), as well as intracellular and secretory protein signaling. Here, we aimed to investigate the PTMs of the apelin receptor (APLNR), a GPCR and their potential influence on the receptor's function. In an in vitro experiment using HEK cells, we only observed glycosylation as a PTM of the APLNR and ineffective receptor signaling by the agonist, (Pyr1)-apelin-13. In contrast, when analyzing mouse spinal cord, we detected glycosylation and other PTMs, excluding isopeptidation. This suggests that additional PTMs are involved in the functional expression of the APLNR in vitro. In summary, these findings suggest that the APLNR in vivo requires multiple PTMs for functional expression. To comprehensively understand the pharmacological effects of the APLNR, it is essential to establish an in vitro system that adequately replicates the receptor's PTM profile. Nonetheless, it is crucial to overcome the challenge of heat-sensitive proteolysis in APLNR studies. By elucidating the regulation of PTMs, further research has the potential to advance the analysis and pharmacological studies of both the apelin/APLNR system and GPCR signal modulation.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Nobuyuki Kuramoto
- Laboratory of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka 573-0101, Japan
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11
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El-Latif AMA, Rabie MA, Sayed RH, Fattah MAAE, Kenawy SA. Inosine attenuates rotenone-induced Parkinson's disease in rats by alleviating the imbalance between autophagy and apoptosis. Drug Dev Res 2023; 84:1159-1174. [PMID: 37170799 DOI: 10.1002/ddr.22077] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 03/24/2023] [Accepted: 04/03/2023] [Indexed: 05/13/2023]
Abstract
Growing evidence points to impaired autophagy as one of the major factors implicated in the pathophysiology of Parkinson's disease (PD). Autophagy is a downstream target of adenosine monophosphate-activated protein kinase (AMPK). Inosine has already demonstrated a neuroprotective effect against neuronal loss in neurodegenerative diseases, mainly due its anti-inflammatory and antioxidant properties. We, herein, aimed at investigating the neuroprotective effects of inosine against rotenone-induced PD in rats and to focus on the activation of AMPK-mediated autophagy. Inosine successfully increased p-AMPK/AMPK ratio in PD rats and improved their motor performance and muscular co-ordination (assessed by rotarod, open field, and grip strength tests, as well as by manual gait analysis). Furthermore, inosine was able to mitigate the rotenone-induced histopathological alterations and to restore the tyrosine hydroxylase immunoreactivity in PD rats' substantia nigra. Inosine-induced AMPK activation resulted in an autophagy enhancement, as demonstrated by the increased striatal Unc-S1-like kinase1 and beclin-1 expression, and also by the increment light chain 3II to light chain 3I ratio, along with the decline in striatal mammalian target of rapamycin and p62 protein expressions. The inosine-induced stimulation of AMPK also attenuated neuronal apoptosis and promoted antioxidant activity. Unsurprisingly, these neuroprotective effects were antagonized by a preadministration of dorsomorphin (an AMPK inhibitor). In conclusion, inosine exerted neuroprotective effects against the rotenone-induced neuronal loss via an AMPK activation and through the restoration of the imbalance between autophagy and apoptosis. These findings support potential application of inosine in PD treatment.
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Affiliation(s)
- Aya M Abd El-Latif
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mostafa A Rabie
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Rabab H Sayed
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mai A Abd El Fattah
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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12
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Tureček R, Melichar A, Králíková M, Hrušková B. The role of GABA B receptors in the subcortical pathways of the mammalian auditory system. Front Endocrinol (Lausanne) 2023; 14:1195038. [PMID: 37635966 PMCID: PMC10456889 DOI: 10.3389/fendo.2023.1195038] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 07/24/2023] [Indexed: 08/29/2023] Open
Abstract
GABAB receptors are G-protein coupled receptors for the inhibitory neurotransmitter GABA. Functional GABAB receptors are formed as heteromers of GABAB1 and GABAB2 subunits, which further associate with various regulatory and signaling proteins to provide receptor complexes with distinct pharmacological and physiological properties. GABAB receptors are widely distributed in nervous tissue, where they are involved in a number of processes and in turn are subject to a number of regulatory mechanisms. In this review, we summarize current knowledge of the cellular distribution and function of the receptors in the inner ear and auditory pathway of the mammalian brainstem and midbrain. The findings suggest that in these regions, GABAB receptors are involved in processes essential for proper auditory function, such as cochlear amplifier modulation, regulation of spontaneous activity, binaural and temporal information processing, and predictive coding. Since impaired GABAergic inhibition has been found to be associated with various forms of hearing loss, GABAB dysfunction could also play a role in some pathologies of the auditory system.
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Affiliation(s)
- Rostislav Tureček
- Department of Auditory Neuroscience, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czechia
| | - Adolf Melichar
- Department of Auditory Neuroscience, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czechia
- Second Faculty of Medicine, Charles University, Prague, Czechia
| | - Michaela Králíková
- Department of Auditory Neuroscience, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czechia
| | - Bohdana Hrušková
- Department of Auditory Neuroscience, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czechia
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13
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Barrett CE, Jiang M, O'Flaherty BG, Dias BG, Rainnie DG, Young LJ, Menigoz A. Early life exposure to high fructose diet induces metabolic dysregulation associated with sex-specific cognitive impairment in adolescent rats. J Nutr Biochem 2023; 114:109220. [PMID: 36435289 PMCID: PMC9992084 DOI: 10.1016/j.jnutbio.2022.109220] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 04/25/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022]
Abstract
The incidence of adolescent mental health disorders is on the rise. Epidemiological studies suggest that poor nutrition is a significant contributor to this public health crisis, specifically through exposure to high level of dietary sugar, including fructose, during critical periods of development. Previous studies have shown that elevated fructose exposure during adolescence disrupts mental health. Despite these data, it is currently unknown how fructose exposure, specifically during infancy, may impact adolescent mental health. We developed a rat experimental protocol to investigate the effects of fructose exposure during infancy on behavioral, cognitive and metabolic endpoints in adolescence. We found that exposing rats to high fructose from birth to weaning resulted in higher circulating glucose, insulin and leptin levels in adolescence. High fructose during infancy also increased bodyweight, disrupted metabolic homeostasis in the basolateral amygdala (BLA) as indicated by decreased activity of the cellular energy sensor AMPK, and impaired attention and impulsivity in a male-specific manner. This impaired attention observed in adolescent male rats following neonatal fructose exposure was partially rescued by viral-mediated, in vivo expression of a constitutively active form of AMPK in principal neurons of the BLA. Our results suggest that exposure to high level of fructose during infancy may impact adolescent mental health in a male-specific manner and that manipulation of AMPK activity may mitigate this impact.
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Affiliation(s)
- Catherine E Barrett
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
| | - Megan Jiang
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
| | - Brendan G O'Flaherty
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
| | - Brian G Dias
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA; Department of Pediatrics, Keck School of Medicine of USC, Los Angeles, California, USA; Division of Research on Children, Youth & Families, Children's Hospital Los Angeles, Los Angeles, California, USA; Developmental Neuroscience and Neurogenetics Program, The Saban Research Institute, Los Angeles, California, USA
| | - Donald G Rainnie
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
| | - Larry J Young
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA
| | - Aurelie Menigoz
- Center for Translational Social Neuroscience, Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
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14
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Caniceiro AB, Bueschbell B, Schiedel AC, Moreira IS. Class A and C GPCR Dimers in Neurodegenerative Diseases. Curr Neuropharmacol 2022; 20:2081-2141. [PMID: 35339177 PMCID: PMC9886835 DOI: 10.2174/1570159x20666220327221830] [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: 09/14/2021] [Revised: 02/21/2022] [Accepted: 03/23/2022] [Indexed: 11/22/2022] Open
Abstract
Neurodegenerative diseases affect over 30 million people worldwide with an ascending trend. Most individuals suffering from these irreversible brain damages belong to the elderly population, with onset between 50 and 60 years. Although the pathophysiology of such diseases is partially known, it remains unclear upon which point a disease turns degenerative. Moreover, current therapeutics can treat some of the symptoms but often have severe side effects and become less effective in long-term treatment. For many neurodegenerative diseases, the involvement of G proteincoupled receptors (GPCRs), which are key players of neuronal transmission and plasticity, has become clearer and holds great promise in elucidating their biological mechanism. With this review, we introduce and summarize class A and class C GPCRs, known to form heterodimers or oligomers to increase their signalling repertoire. Additionally, the examples discussed here were shown to display relevant alterations in brain signalling and had already been associated with the pathophysiology of certain neurodegenerative diseases. Lastly, we classified the heterodimers into two categories of crosstalk, positive or negative, for which there is known evidence.
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Affiliation(s)
- Ana B. Caniceiro
- Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504 Coimbra, Portugal; ,These authors contributed equally to this work.
| | - Beatriz Bueschbell
- PhD Programme in Experimental Biology and Biomedicine, Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão, 3030-789 Coimbra, Portugal; ,These authors contributed equally to this work.
| | - Anke C. Schiedel
- Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, D-53121 Bonn, Germany;
| | - Irina S. Moreira
- University of Coimbra, Department of Life Sciences, Calçada Martim de Freitas, 3000-456 Coimbra, Portugal; ,Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal,Address correspondence to this author at the Center for Neuroscience and Cell Biology, Center for Innovative Biomedicine and Biotechnology, 3004-504 Coimbra, Portugal; E-mail:
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15
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Hleihil M, Balakrishnan K, Benke D. Protein phosphatase 2A regulation of GABAB receptors normalizes ischemia-induced aberrant receptor trafficking and provides neuroprotection. Front Mol Neurosci 2022; 15:1015906. [PMID: 36311027 PMCID: PMC9607930 DOI: 10.3389/fnmol.2022.1015906] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/26/2022] [Indexed: 11/13/2022] Open
Abstract
One major factor regulating the strength of GABAB receptor signaling and thereby neuronal excitability is the dynamic control of their cell surface expression. GABAB receptors are constitutively internalized and recycled back to the plasma membrane to maintain a stable number of receptors at cell surface for appropriate signaling. Protein phosphatase 2A (PP2A) dependent dephosphorylation of serine 783 (S783) in the GABAB2 subunit is a key event for downregulating GABAB receptor cell surface expression particularly under conditions associated with excitotoxicity. Here, we investigated the role of PP2A in regulating GABAB receptor cell surface expression under physiological and excitotoxic conditions. For this purpose, we developed an interfering peptide (PP2A-Pep) that inhibits the interaction of GABAB receptors with PP2A. Using cultured cortical neurons, we found that PP2A downregulates GABAB receptor cell surface expression by inhibiting recycling of the receptors and thereby promoting degradation of the receptors. Inhibition of the GABAB receptor/PP2A interaction by PP2A-Pep in cultured cortical neurons restored GABAB receptor cell surface expression after excitotoxic stress and inhibited progressing neuronal death even when added 48 h after the insult. To explore the therapeutic potential of PP2A-Pep, we further analyzed effect of PP2A-Pep in the middle cerebral artery occlusion (MCAO) mouse model of cerebral ischemia. Incubation of brain slices prepared from MCAO-treated mice with PP2A-Pep restored normal GABAB receptor expression and GABAB receptor-mediated inhibition, reduced ischemic-induced overexcitability of neurons, and prevented neuronal death in the ischemic penumbra. This data illustrates the crucial role of regulating GABAB receptor phosphorylation by PP2A for controlling neuronal inhibition and excitability. The results further suggest that interfering with the GABAB receptor/PP2A interaction is a promising strategy for the development of specific therapeutic interventions to treat neurological diseases associated with a disturbed excitation/inhibition balance and downregulation of GABAB receptors.
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Affiliation(s)
- Mohammad Hleihil
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and ETH Zürich, Zurich, Switzerland
| | - Karthik Balakrishnan
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
| | - Dietmar Benke
- Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
- Neuroscience Center Zurich, University of Zurich and ETH Zürich, Zurich, Switzerland
- Drug Discovery Network Zurich, Zurich, Switzerland
- *Correspondence: Dietmar Benke,
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16
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Kamel AS, Wahid A, Abdelkader NF, Ibrahim WW. Boosting amygdaloid GABAergic and neurotrophic machinery via dapagliflozin-enhanced LKB1/AMPK signaling in anxious demented rats. Life Sci 2022; 310:121002. [PMID: 36191679 DOI: 10.1016/j.lfs.2022.121002] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/18/2022]
Abstract
Anxiety is a neuropsychiatric disturbance that is commonly manifested in various dementia forms involving Alzheimer's disease (AD). The mechanisms underlying AD-associated anxiety haven't clearly recognized the role of energy metabolism in anxiety represented by the amygdala's autophagic sensors; liver kinase B1 (LKB1)/adenosine monophosphate kinase (AMPK). Dapagliflozin (DAPA), a SGLT2 inhibitor, acts as an autophagic activator through LKB1 activation in several diseases including AD. Herein, the propitious yet undetected anxiolytic potential of DAPA as an autophagic enhancer was investigated in AD animal model with emphasis on amygdala's GABAergic neurotransmission and brain-derived neurotrophic factor (BDNF). Alzheimer's disease was induced by ovariectomy (OVX) along with seventy-days-D-galactose (D-Gal) administration (150 mg/kg/day, i.p). On the 43rd day of D-Gal injection, OVX/D-Gal-subjected rats received DAPA (1 mg/kg/day, p.o) alone or with dorsomorphin the AMPK inhibitor (DORSO, 25 μg/rat, i.v.). In the amygdala, LKB1/AMPK were activated by DAPA inducing GABAB2 receptor stimulation; an effect that was abrogated by DORSO. Dapagliflozin also replenished the amygdala GABA, NE, and 5-HT levels along with glutamate suppression. Moreover, DAPA triggered BDNF production with consequent activation of its receptor, TrkB through activating GABAB2-related downstream phospholipase C/diacylglycerol/protein kinase C (PLC/DAG/PKC) signaling. This may promote GABAA expression, verifying the crosstalk between GABAA and GABAB2. The DAPA's anxiolytic effect was visualized by improved behavioral traits in elevated plus maze together with amendment of amygdala' histopathological abnormalities. Thus, the present study highlighted DAPA's anxiolytic effect which was attributed to GABAB2 activation and its function to induce BDNF/TrkB and GABAA expression through PLC/DAG/PKC pathway in AMPK-dependent manner.
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Affiliation(s)
- Ahmed S Kamel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
| | - Ahmed Wahid
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Alexandria University, Egypt
| | - Noha F Abdelkader
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt.
| | - Weam W Ibrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Egypt
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17
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Onishi Y, Yamamura Y, Hosogi M, Higashi H, Ogita K, Kinjo T, Uno K, Yoneda Y, Kuramoto N. Delayed Expression of Both GABA BR1 and GABA BR2 Subunits in Murine Hippocampal Dentate Gyrus After a Single Systemic Injection of Trimethyltin. Neurochem Res 2022; 47:2780-2792. [PMID: 35737203 DOI: 10.1007/s11064-022-03652-7] [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: 03/31/2022] [Revised: 05/26/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022]
Abstract
Trimethyltin (TMT) has been used as a cytotoxin to neurons rather than glial cells in the mammalian hippocampus. The systemic administration of TMT led to declined fluorescence of ZnAF-2 DA staining as a marker of intact mossy fibers and increased fluorescence of Fluoro-Jade B staining as a marker of degenerated neurons during the initial 2 to 5 days after the administration with later ameliorations within 30 days in the hippocampal dentate gyrus (DG) and CA3 region in mice. On immunoblotting analysis, both GABABR1 and GABABR2 subunit levels increased during 15 to 30 days after TMT along with significant decreases in glutamatergic GluA1 and GluA2/3 receptor subunit levels during 2 to 7 days in the DG, but not in other hippocampal regions such as CA1 and CA3 regions. Immunohistochemical analysis revealed the constitutive and inducible expression of GABABR2 subunit in cells immunoreactive to an astrocytic marker as well as neuronal markers in the DG with the absence of neither GABABR1a nor GABABR1b subunit from cells positive to an astrocytic marker. These results suggest that both GABABR1 and GABABR2 subunits may be up-regulated in cells other than neurons and astroglia in the DG at a late stage of TMT intoxication in mice.
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Affiliation(s)
- Yuki Onishi
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan
- Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, 737-0112, Japan
| | - Yusuke Yamamura
- Laboratories of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
| | - Misa Hosogi
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan
| | - Hiroshi Higashi
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan
| | - Kiyokazu Ogita
- Laboratories of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan
- Setsunan University, 17-8 Ikedanakamachi, Neyagawa, Osaka, 572-8508, Japan
| | - Toshihiko Kinjo
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan
| | - Kyosuke Uno
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan
| | - Yukio Yoneda
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan
| | - Nobuyuki Kuramoto
- Laboratories of Molecular Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan.
- Laboratories of Pharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Hirakata, Osaka, 573-0101, Japan.
- The Institute of Prophylactic Pharmacology, Kita-Shinagawa, Shinagawa, Tokyo, 140-0001, Japan.
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18
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Heidary Moghaddam R, Samimi Z, Asgary S, Mohammadi P, Hozeifi S, Hoseinzadeh-Chahkandak F, Xu S, Farzaei MH. Natural AMPK Activators in Cardiovascular Disease Prevention. Front Pharmacol 2022; 12:738420. [PMID: 35046800 PMCID: PMC8762275 DOI: 10.3389/fphar.2021.738420] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 11/03/2021] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular diseases (CVD), as a life-threatening global disease, is receiving worldwide attention. Seeking novel therapeutic strategies and agents is of utmost importance to curb CVD. AMP-activated protein kinase (AMPK) activators derived from natural products are promising agents for cardiovascular drug development owning to regulatory effects on physiological processes and diverse cardiometabolic disorders. In the past decade, different therapeutic agents from natural products and herbal medicines have been explored as good templates of AMPK activators. Hereby, we overviewed the role of AMPK signaling in the cardiovascular system, as well as evidence implicating AMPK activators as potential therapeutic tools. In the present review, efforts have been made to compile and update relevant information from both preclinical and clinical studies, which investigated the role of natural products as AMPK activators in cardiovascular therapeutics.
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Affiliation(s)
- Reza Heidary Moghaddam
- Clinical Research Development Center, Imam Ali and Taleghani Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Zeinab Samimi
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Sedigheh Asgary
- Isfahan Cardiovascular Research Center, Cardiovascular Research Institute,.Isfahan University of Medical Sciences, Isfahan, Iran
| | - Pantea Mohammadi
- Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Soroush Hozeifi
- School of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Suowen Xu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Medical Technology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
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19
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Salvati KA, Ritger ML, Davoudian PA, O’Dell F, Wyskiel DR, Souza GMPR, Lu AC, Perez-Reyes E, Drake JC, Yan Z, Beenhakker MP. OUP accepted manuscript. Brain 2022; 145:2332-2346. [PMID: 35134125 PMCID: PMC9337815 DOI: 10.1093/brain/awac037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 12/20/2021] [Accepted: 12/26/2021] [Indexed: 11/21/2022] Open
Abstract
Metabolism regulates neuronal activity and modulates the occurrence of epileptic seizures. Here, using two rodent models of absence epilepsy, we show that hypoglycaemia increases the occurrence of spike-wave seizures. We then show that selectively disrupting glycolysis in the thalamus, a structure implicated in absence epilepsy, is sufficient to increase spike-wave seizures. We propose that activation of thalamic AMP-activated protein kinase, a sensor of cellular energetic stress and potentiator of metabotropic GABAB-receptor function, is a significant driver of hypoglycaemia-induced spike-wave seizures. We show that AMP-activated protein kinase augments postsynaptic GABAB-receptor-mediated currents in thalamocortical neurons and strengthens epileptiform network activity evoked in thalamic brain slices. Selective thalamic AMP-activated protein kinase activation also increases spike-wave seizures. Finally, systemic administration of metformin, an AMP-activated protein kinase agonist and common diabetes treatment, profoundly increased spike-wave seizures. These results advance the decades-old observation that glucose metabolism regulates thalamocortical circuit excitability by demonstrating that AMP-activated protein kinase and GABAB-receptor cooperativity is sufficient to provoke spike-wave seizures.
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Affiliation(s)
- Kathryn A Salvati
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
- Epilepsy Research Laboratory and Weil Institute for Neurosciences, Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Matthew L Ritger
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Pasha A Davoudian
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
- MD-PhD Program, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Finnegan O’Dell
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Daniel R Wyskiel
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - George M P R Souza
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Adam C Lu
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Edward Perez-Reyes
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Joshua C Drake
- Department of Human Nutrition, Foods and Exercise, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA
- The Robert M. Berne Center for Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Zhen Yan
- Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
- The Robert M. Berne Center for Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
- Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA
- Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA
| | - Mark P Beenhakker
- Correspondence to: Mark P. Beenhakker Department of Pharmacology University of Virginia School of Medicine Charlottesville, VA, 22908, USA E-mail:
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20
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Insulin-like growth factor I mitigates post-traumatic stress by inhibiting AMP-kinase in orexin neurons. Mol Psychiatry 2022; 27:2182-2196. [PMID: 35115701 PMCID: PMC9126821 DOI: 10.1038/s41380-022-01442-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 12/14/2021] [Accepted: 01/11/2022] [Indexed: 12/21/2022]
Abstract
Maladaptive coping behaviors are probably involved in post-traumatic stress disorders (PTSD), but underlying mechanisms are incompletely understood. We now report that mice lacking functional insulin-like growth factor I (IGF-I) receptors in orexin neurons of the lateral hypothalamus (Firoc mice) are unresponsive to the anxiolytic actions of IGF-I and develop PTSD-like behavior that is ameliorated by inhibition of orexin neurons. Conversely, systemic IGF-I treatment ameliorated PTSD-like behavior in a wild-type mouse model of PTSD (PTSD mice). Further, systemic IGF-I modified the GABA/Glutamate synaptic structure in orexin neurons of naïve wild-type mice by increasing the dephosphorylation of GABA(B) receptor subunit through inhibition of AMP-kinase (AMPK). Significantly, pharmacological inhibition of AMPK mimicked IGF-I, normalizing fear behavior in PTSD mice. Thus, we suggest that IGF-I enables coping behaviors by balancing E/I input onto orexin neurons in a context-dependent manner. These observations provide a novel therapeutic approach to PTSD through modulation of AMPK.
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21
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Wei B, Zhu Y, Yang P, Han Y, Wang S, Wang X, Xia S, Song X, Zhang Z, Wang S, Rondard P, Pin JP, Jiang X, Liu J. GABA B1e promotes the malignancy of human cancer cells by targeting the tyrosine phosphatase PTPN12. iScience 2021; 24:103311. [PMID: 34778730 PMCID: PMC8577127 DOI: 10.1016/j.isci.2021.103311] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/24/2021] [Accepted: 10/14/2021] [Indexed: 01/30/2023] Open
Abstract
Neurotransmitter receptors are involved in cancer progression. Among them, the heterodimeric GABAB receptor, activated by the main inhibitory neurotransmitter GABA, is composed of the transmembrane GABAB1 and GABAB2 subunits. The oncogenic role of the isoform GABAB1e (GB1e) containing only the extracellular domain of GABAB1 remains unclear. We revealed that GB1e is largely expressed in human breast cancer (BrCa) cell lines as well as in BrCa tissues where it is upregulated. Moreover, GB1e promoted the malignancy of BrCa cells both in vitro and in vivo. We propose that GB1e favors EGFR signaling by interacting with PTPN12 to disrupt the interaction between EGFR and PTPN12, and phosphorylation of Y230 and Y404 on GB1e is required in this process. Our data highlight that the GABBR1 gene through the expression of the GB1e isoform might play an important oncogenic role in BrCa and that GB1e is of interest for the treatment of some cancers.
GABAB1e promotes the malignancy of breast cancer cells both in vitro and in vivo Specific phosphorylation of GABAB1e is critical for its association with PTPN12 GABAB1e disrupts EGFR interacting with PTPN12 and induces EGFR-PI3K/Akt signaling
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Affiliation(s)
- Bo Wei
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Yini Zhu
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Peng Yang
- Department of Breast & Endocrine Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China
| | - Yong Han
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China
| | - Suyun Wang
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Xiaomei Wang
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Shuai Xia
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Xiaoguang Song
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Zhongling Zhang
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Sheng Wang
- Key Laboratory of Molecular Biophysics of MOE, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
| | - Philippe Rondard
- Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, 34094 Montpellier, France
| | - Jean-Philippe Pin
- Institut de Génomique Fonctionnelle (IGF), Université de Montpellier, CNRS, INSERM, 34094 Montpellier, France
| | - Xinnong Jiang
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
- Corresponding author
| | - Jianfeng Liu
- Key Laboratory of Molecular Biophysics of MOE, International Research Center for Sensory Biology and Technology of MOST, College of Life Science and Technology, Huazhong University of Science and Technology (HUST), Wuhan 430074, China
- Corresponding author
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22
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Salsaa M, Aziz K, Lazcano P, Schmidtke MW, Tarsio M, Hüttemann M, Reynolds CA, Kane PM, Greenberg ML. Valproate activates the Snf1 kinase in Saccharomyces cerevisiae by decreasing the cytosolic pH. J Biol Chem 2021; 297:101110. [PMID: 34428448 PMCID: PMC8449051 DOI: 10.1016/j.jbc.2021.101110] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 11/27/2022] Open
Abstract
Valproate (VPA) is a widely used mood stabilizer, but its therapeutic mechanism of action is not understood. This knowledge gap hinders the development of more effective drugs with fewer side effects. Using the yeast model to elucidate the effects of VPA on cellular metabolism, we determined that the drug upregulated expression of genes normally repressed during logarithmic growth on glucose medium and increased levels of activated (phosphorylated) Snf1 kinase, the major metabolic regulator of these genes. VPA also decreased the cytosolic pH (pHc) and reduced glycolytic production of 2/3-phosphoglycerate. ATP levels and mitochondrial membrane potential were increased, and glucose-mediated extracellular acidification decreased in the presence of the drug, as indicated by a smaller glucose-induced shift in pH, suggesting that the major P-type proton pump Pma1 was inhibited. Interestingly, decreasing the pHc by omeprazole-mediated inhibition of Pma1 led to Snf1 activation. We propose a model whereby VPA lowers the pHc causing a decrease in glycolytic flux. In response, Pma1 is inhibited and Snf1 is activated, resulting in increased expression of normally repressed metabolic genes. These findings suggest a central role for pHc in regulating the metabolic program of yeast cells.
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Affiliation(s)
- Michael Salsaa
- Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA
| | - Kerestin Aziz
- Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA
| | - Pablo Lazcano
- Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA
| | - Michael W Schmidtke
- Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA
| | - Maureen Tarsio
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Maik Hüttemann
- Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, Michigan, USA
| | - Christian A Reynolds
- Department of Emergency Medicine, School of Medicine, Wayne State University, Detroit, Michigan, USA; Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Patricia M Kane
- Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Miriam L Greenberg
- Department of Biological Sciences, Wayne State University, Detroit, Michigan, USA.
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23
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Muraleedharan R, Dasgupta B. AMPK in the brain: its roles in glucose and neural metabolism. FEBS J 2021; 289:2247-2262. [PMID: 34355526 DOI: 10.1111/febs.16151] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/22/2021] [Accepted: 08/04/2021] [Indexed: 11/28/2022]
Abstract
The adenosine monophosphate-activated protein kinase (AMPK) is an integrative metabolic sensor that maintains energy balance at the cellular level and plays an important role in orchestrating intertissue metabolic signaling. AMPK regulates cell survival, metabolism, and cellular homeostasis basally as well as in response to various metabolic stresses. Studies so far show that the AMPK pathway is associated with neurodegeneration and CNS pathology, but the mechanisms involved remain unclear. AMPK dysregulation has been reported in neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and other neuropathies. AMPK activation appears to be both neuroprotective and pro-apoptotic, possibly dependent upon neural cell types, the nature of insults, and the intensity and duration of AMPK activation. While embryonic brain development in AMPK null mice appears to proceed normally without any overt structural abnormalities, our recent study confirmed the full impact of AMPK loss in the postnatal and aging brain. Our studies revealed that Ampk deletion in neurons increased basal neuronal excitability and reduced latency to seizure upon stimulation. Three major pathways, glycolysis, pentose phosphate shunt, and glycogen turnover, contribute to utilization of glucose in the brain. AMPK's regulation of aerobic glycolysis in astrocytic metabolism warrants further deliberation, particularly glycogen turnover and shuttling of glucose- and glycogen-derived lactate from astrocytes to neurons during activation. In this minireview, we focus on recent advances in AMPK and energy-sensing in the brain.
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Affiliation(s)
| | - Biplab Dasgupta
- Division of Oncology, Cincinnati Children's Hospital Medical Center, OH, USA
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24
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Xie X, Zhang Y, Wang Z, Wang S, Jiang X, Cui H, Zhou T, He Z, Feng H, Guo Q, Song X, Cao L. ATM at the crossroads of reactive oxygen species and autophagy. Int J Biol Sci 2021; 17:3080-3090. [PMID: 34421351 PMCID: PMC8375236 DOI: 10.7150/ijbs.63963] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 07/16/2021] [Indexed: 01/08/2023] Open
Abstract
Reactive oxygen species (ROS) are generally small, short-lived and highly reactive molecules, initially thought to be a pathological role in the cell. A growing amount of evidence in recent years argues for ROS functioning as a signaling intermediate to facilitate cellular adaptation in response to pathophysiological stress through the regulation of autophagy. Autophagy is an essential cellular process that plays a crucial role in recycling cellular components and damaged organelles to eliminate sources of ROS in response to various stress conditions. A large number of studies have shown that DNA damage response (DDR) transducer ataxia-telangiectasia mutated (ATM) protein can also be activated by ROS, and its downstream signaling pathway is involved in autophagy regulation. This review aims at providing novel insight into the regulatory mechanism of ATM activated by ROS and its molecular basis for inducing autophagy, and revealing a new function that ATM can not only maintain genome homeostasis in the nucleus, but also as a ROS sensor trigger autophagy to maintain cellular homeostasis in the cytoplasm.
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Affiliation(s)
- Xiaochen Xie
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
- Department of Endocrinology and Metabolism, Institute of Endocrinology, Liaoning Provincial Key Laboratory of Endocrine Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, Liaoning, 110001, P. R. China
| | - Ye Zhang
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Zhuo Wang
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Shanshan Wang
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Xiaoyou Jiang
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Hongyan Cui
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Tingting Zhou
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Zheng He
- Department of Radiation Oncology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China
| | - Hao Feng
- Department of Ophthalmology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, 110001, P. R. China
| | - Qiqiang Guo
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Xiaoyu Song
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
| | - Liu Cao
- College of Basic Medical Science, Key Laboratory of Medical Cell Biology, Ministry of Education, Key Laboratory of Liaoning Province, China Medical University, Shenyang, Liaoning Province, 110122, P. R. China
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25
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AMPK-Regulated Astrocytic Lactate Shuttle Plays a Non-Cell-Autonomous Role in Neuronal Survival. Cell Rep 2021; 32:108092. [PMID: 32877674 PMCID: PMC7531170 DOI: 10.1016/j.celrep.2020.108092] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 07/01/2020] [Accepted: 08/07/2020] [Indexed: 12/18/2022] Open
Abstract
Lactate is used as an energy source by producer cells or shuttled to neighboring cells and tissues. Both glucose and lactate fulfill the bioenergetic demand of neurons, the latter imported from astrocytes. The contribution of astrocytic lactate to neuronal bioenergetics and the mechanisms of astrocytic lactate production are incompletely understood. Through in vivo1H magnetic resonance spectroscopy, 13C glucose mass spectroscopy, and electroencephalographic and molecular studies, here we show that the energy sensor AMP activated protein kinase (AMPK) regulates neuronal survival in a non-cell-autonomous manner. Ampk-null mice are deficient in brain lactate and are seizure prone. Ampk deletion in astroglia, but not neurons, causes neuronal loss in both mammalian and fly brains. Mechanistically, astrocytic AMPK phosphorylated and destabilized thioredoxin-interacting protein (TXNIP), enabling expression and surface translocation of the glucose transporter GLUT1, glucose uptake, and lactate production. Ampk loss in astrocytes causes TXNIP hyperstability, GLUT1 misregulation, inadequate glucose metabolism, and neuronal loss. Muraleedharan et al. demonstrate that AMPK is required for astrocytic glycolysis, lactate production, and lactate shuttle as an energy source to neurons such that AMPK loss in glia causes non-cell-autonomous neuronal loss in the mammalian and fly brain.
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26
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Grissi M, Boudot C, Assem M, Candellier A, Lando M, Poirot-Leclercq S, Boullier A, Bennis Y, Lenglet G, Avondo C, Lalau JD, Choukroun G, Massy ZA, Kamel S, Chillon JM, Hénaut L. Metformin prevents stroke damage in non-diabetic female mice with chronic kidney disease. Sci Rep 2021; 11:7464. [PMID: 33811249 PMCID: PMC8018962 DOI: 10.1038/s41598-021-86905-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 03/17/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic kidney disease (CKD) worsens ischemic stroke severity in both patients and animals. In mice, these poorer functional outcomes are associated with decreased brain activity of AMP-activated protein kinase (AMPK), a molecule that recently emerged as a potential therapeutic target for ischemic stroke. The antidiabetic drug metformin, a well-known activator of AMPK, has improved stroke outcomes in diabetic patients with normal renal function. We investigated whether chronic metformin pre-conditioning can rescue AMPK activity and prevent stroke damage in non-diabetic mice with CKD. Eight-week-old female C57BL/6J mice were assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery, followed by left total nephrectomy. Mice were then allocated to receive metformin (200 mg/kg/day) or vehicle for 5 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). The infarct volumes were lower in CKD mice exposed to metformin than in vehicle-treated CKD mice 24 h after tMCAO. Metformin pre-conditioning of CKD mice improved their neurological score, grip strength, and prehensile abilities. It also enhanced AMPK activation, reduced apoptosis, increased neuron survival and decreased microglia/macrophage M1 signature gene expression as well as CKD-induced activation of the canonical NF-κB pathway in the ischemic lesions of CKD mice.
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MESH Headings
- Adenylate Kinase/metabolism
- Animals
- Apoptosis/drug effects
- Body Weight
- Brain Infarction/blood
- Brain Infarction/complications
- Brain Infarction/drug therapy
- Brain Infarction/genetics
- Enzyme Activation/drug effects
- Female
- Gene Expression Regulation
- Gliosis/blood
- Gliosis/complications
- Gliosis/drug therapy
- Infarction, Middle Cerebral Artery/blood
- Infarction, Middle Cerebral Artery/complications
- Infarction, Middle Cerebral Artery/drug therapy
- Infarction, Middle Cerebral Artery/genetics
- Ischemic Preconditioning
- Macrophages/drug effects
- Macrophages/pathology
- Metformin/blood
- Metformin/pharmacology
- Metformin/therapeutic use
- Mice, Inbred C57BL
- Microglia/drug effects
- Microglia/pathology
- Models, Biological
- NF-kappa B/metabolism
- Neurons/drug effects
- Neurons/pathology
- Renal Insufficiency, Chronic/blood
- Renal Insufficiency, Chronic/complications
- Renal Insufficiency, Chronic/drug therapy
- Renal Insufficiency, Chronic/genetics
- Stroke/drug therapy
- Stroke/genetics
- Stroke/prevention & control
- Mice
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Affiliation(s)
- Maria Grissi
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
| | - Cédric Boudot
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
| | - Maryam Assem
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Division of Nephrology, Amiens University Hospital, 80054, Amiens, France
| | - Alexandre Candellier
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Division of Nephrology, Amiens University Hospital, 80054, Amiens, France
| | - Mathilde Lando
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Division of Nephrology, Amiens University Hospital, 80054, Amiens, France
| | - Sabrina Poirot-Leclercq
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
| | - Agnès Boullier
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Department of Biochemistry, Amiens University Hospital, 80054, Amiens, France
| | - Youssef Bennis
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Department of Clinical Pharmacology, Amiens University Hospital, 80054, Amiens, France
| | - Gaëlle Lenglet
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
| | - Carine Avondo
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
| | - Jean-Daniel Lalau
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Department of Endocrinology-Diabetology-Nutrition, Amiens University Hospital, 80054, Amiens, France
- UMR_I 01, PériTox, CURS, 80054, Amiens, France
| | - Gabriel Choukroun
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Medicine, University of Picardie Jules Verne, 80000, Amiens, France
- Division of Nephrology, Amiens University Hospital, 80054, Amiens, France
| | - Ziad A Massy
- Department of Nephrology, Ambroise Paré University Hospital, APHP, 92104, Boulogne-Billancourt, France
- Inserm U1018-Team 5, CESP, UVSQ, University Paris Saclay, 94807, Villejuif, France
- University Versailles-Saint Quentin, University Paris-Saclay, 91190, Villejuif, France
| | - Saïd Kamel
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Department of Biochemistry, Amiens University Hospital, 80054, Amiens, France
- Faculty of Pharmacy, University of Picardie Jules Verne, 80000, Amiens, France
| | - Jean-Marc Chillon
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France
- Faculty of Pharmacy, University of Picardie Jules Verne, 80000, Amiens, France
- Direction of Clinical Research, Amiens University Hospital, 80054, Amiens, France
| | - Lucie Hénaut
- UR UPJV 7517, MP3CV, CURS, Université de Picardie Jules Verne, Avenue René Laennec, 80054, Amiens, France.
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27
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Hamad MIK, Jbara A, Rabaya O, Petrova P, Daoud S, Melliti N, Meseke M, Lutz D, Petrasch-Parwez E, Schwitalla JC, Mark MD, Herlitze S, Reiss G, Herz J, Förster E. Reelin signaling modulates GABA B receptor function in the neocortex. J Neurochem 2021; 156:589-603. [PMID: 32083308 PMCID: PMC7442713 DOI: 10.1111/jnc.14990] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 01/27/2020] [Accepted: 02/18/2020] [Indexed: 11/27/2022]
Abstract
Reelin is a protein that is best known for its role in controlling neuronal layer formation in the developing cortex. Here, we studied its role for post-natal cortical network function, which is poorly explored. To preclude early cortical migration defects caused by Reelin deficiency, we used a conditional Reelin knock-out (RelncKO ) mouse, and induced Reelin deficiency post-natally. Induced Reelin deficiency caused hyperexcitability of the neocortical network in vitro and ex vivo. Blocking Reelin binding to its receptors ApoER2 and VLDLR resulted in a similar effect. Hyperexcitability in RelncKO organotypic slice cultures could be rescued by co-culture with wild-type organotypic slice cultures. Moreover, the GABAB receptor (GABAB R) agonist baclofen failed to activate and the antagonist CGP35348 failed to block GABAB Rs in RelncKO mice. Immunolabeling of RelncKO cortical slices revealed a reduction in GABAB R1 and GABAB R2 surface expression at the plasma membrane and western blot of RelncKO cortical tissue revealed decreased phosphorylation of the GABAB R2 subunit at serine 892 and increased phosphorylation at serine 783, reflecting receptor deactivation and proteolysis. These data show a role of Reelin in controlling early network activity, by modulating GABAB R function. Cover Image for this issue: https://doi.org/10.1111/jnc.15054.
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Affiliation(s)
- Mohammad I K Hamad
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
- Institute for Anatomy and Clinical Morphology, School of Medicine, Faculty of Health, Herdecke University, Witten, Witten
| | - Abdalrahim Jbara
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Obada Rabaya
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Petya Petrova
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Solieman Daoud
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Nesrine Melliti
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Maurice Meseke
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - David Lutz
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | - Elisabeth Petrasch-Parwez
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
| | | | - Melanie D Mark
- Department of Behavioral Neuroscience, Ruhr University Bochum, Bochum, Germany
| | - Stefan Herlitze
- Department of Zoology and Neurobiology, Ruhr University Bochum, Bochum, Germany
| | - Gebhard Reiss
- Institute for Anatomy and Clinical Morphology, School of Medicine, Faculty of Health, Herdecke University, Witten, Witten
| | - Joachim Herz
- Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, Center for Translational Neurodegeneration Research, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Eckart Förster
- Department of Neuroanatomy and Molecular Brain Research, Ruhr University Bochum, Medical Faculty, Bochum, Germany
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Hossein-Javaheri N, Buck LT. GABA receptor inhibition and severe hypoxia induce a paroxysmal depolarization shift in goldfish neurons. J Neurophysiol 2020; 125:321-330. [PMID: 33296606 DOI: 10.1152/jn.00149.2020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Mammalian neurons undergo rapid excitotoxic cell death when deprived of oxygen; however, the common goldfish (Carassius auratus) has the unique ability of surviving in oxygen-free waters, under anoxia. This organism utilizes γ-amino butyric acid (GABA) signaling to suppress excitatory glutamatergic activity during anoxic periods. Although GABAA receptor antagonists are not deleterious to the cellular survival, coinhibition of GABAA and GABAB receptors is detrimental by abolishing anoxia-induced neuroprotective mechanisms. Here we show that blocking the anoxic GABAergic neurotransmission induces seizure-like activity (SLA) analogous to a paroxysmal depolarization shift (PDS), with hyperpolarization of action potential (AP) threshold and elevation of threshold currents. The observed PDS was attributed to an increase in excitatory postsynaptic currents (EPSCs) that are normally attenuated with decreasing oxygen levels. Furthermore, for the first time, we show that in addition to PDS, some neurons undergo depolarization block and do not generate AP despite a suprathreshold membrane potential. In conclusion, our results indicate that with severe hypoxia and absence of GABA receptor activity, telencephalic neurons of C. auratus manifest a paroxysmal depolarization shift, a key feature of epileptic discharge.NEW & NOTEWORTHY This work shows that the combination of anoxia and inhibition of GABA receptors induces seizure-like activities in goldfish telencephalic pyramidal and stellate neurons. Importantly, to prevent seizure-like activity, an intact GABA-mediated inhibitory pathway is required.
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Affiliation(s)
| | - Leslie Thomas Buck
- Department of Cell & Systems Biology, University of Toronto, Toronto, Ontario, Canada
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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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Extracellular Signal-Regulated Kinases Mediate an Autoregulation of GABA B-Receptor-Activated Whole-Cell Current in Locus Coeruleus Neurons. Sci Rep 2020; 10:7869. [PMID: 32398643 PMCID: PMC7217949 DOI: 10.1038/s41598-020-64292-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 04/09/2020] [Indexed: 11/09/2022] Open
Abstract
The norepinephrine-releasing neurons in the locus coeruleus (LC) are well known to regulate wakefulness/arousal. They display active firing during wakefulness and a decreased discharge rate during sleep. We have previously reported that LC neurons express large numbers of GABAB receptors (GABABRs) located at peri-/extrasynaptic sites and are subject to tonic inhibition due to the continuous activation of GABABRs by ambient GABA, which is significantly higher during sleep than during wakefulness. In this study, we further showed using western blot analysis that the activation of GABABRs with baclofen could increase the level of phosphorylated extracellular signal-regulated kinase 1 (ERK1) in LC tissue. Recordings from LC neurons in brain slices showed that the inhibition of ERK1/2 with U0126 and FR180204 accelerated the decay of whole-cell membrane current induced by prolonged baclofen application. In addition, the inhibition of ERK1/2 also increased spontaneous firing and reduced tonic inhibition of LC neurons after prolonged exposure to baclofen. These results suggest a new role of GABABRs in mediating ERK1-dependent autoregulation of the stability of GABABR-activated whole-cell current, in addition to its well-known effect on gated potassium channels, to cause a tonic current in LC neurons.
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Li X, Terunuma M, Deeb TG, Wiseman S, Pangalos MN, Nairn AC, Moss SJ, Slesinger PA. Direct Interaction of PP2A Phosphatase with GABA B Receptors Alters Functional Signaling. J Neurosci 2020; 40:2808-2816. [PMID: 32111696 PMCID: PMC7117905 DOI: 10.1523/jneurosci.2654-19.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 01/02/2020] [Accepted: 02/18/2020] [Indexed: 01/16/2023] Open
Abstract
Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions.
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Affiliation(s)
- Xiaofan Li
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029
| | - Miho Terunuma
- Division of Oral Biochemistry, Graduate School of Medical and Dental Sciences, Niigata University, 951-8514 Japan
| | - Tarek G Deeb
- Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Shari Wiseman
- Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | | | - Angus C Nairn
- Department Psychiatry, Yale University School of Medicine, New Haven, Connecticut 065019
| | - Stephen J Moss
- Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111,
- Department of Physiology, Pharmacology and Neuroscience, University College, London WC1E 6BT, United Kingdom
| | - Paul A Slesinger
- Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029,
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Kim SH, Yu HS, Park S, Park HG, Ahn YM, Kang UG, Kim YS. Electroconvulsive Seizures Induce Autophagy by Activating the AMPK Signaling Pathway in the Rat Frontal Cortex. Int J Neuropsychopharmacol 2020; 23:42-52. [PMID: 31678999 PMCID: PMC7442404 DOI: 10.1093/ijnp/pyz055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 10/10/2019] [Accepted: 10/31/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND It is uncertain how electroconvulsive therapy-induced generalized seizures exert their potent therapeutic effects on various neuropsychiatric disorders. Adenosine monophosphate-activated protein kinase (AMPK) plays a major role in maintaining metabolic homeostasis and activates autophagic processes via unc-51-like kinase (ULK1). Evidence supports the involvement of autophagy system in the action mechanisms of antidepressants and antipsychotics. The effect of electroconvulsive therapy on autophagy-related signaling requires further clarification. METHODS The effect of electroconvulsive seizure on autophagy and its association with the AMPK signaling pathway were investigated in the rat frontal cortex. Electroconvulsive seizure was provided once per day for 10 days (E10X), and compound C or 3-methyadenine was administered through an intracerebroventricular cannula. Molecular changes were analyzed with immunoblot, immunohistochemistry, and transmission electron microscopy analyses. RESULTS E10X increased p-Thr172-AMPKα immunoreactivity in rat frontal cortex neurons. E10X increased phosphorylation of upstream effectors of AMPK, such as LKB1, CaMKK, and TAK1, and of its substrates, ACC, HMGR, and GABABR2. E10X also increased p-Ser317-ULK1 immunoreactivity. At the same time, LC3-II and ATG5-ATG12 conjugate immunoreactivity increased, indicating activation of autophagy. An intracerebroventricular injection of the AMPK inhibitor compound C attenuated the electroconvulsive seizure-induced increase in ULK1 phosphorylation as well as the protein levels of LC3-II and Atg5-Atg12 conjugate. Transmission electron microscopy clearly showed an increased number of autophagosomes in the rat frontal cortex after E10X, which was reduced by intracerebroventricular treatment with the autophagy inhibitor 3-methyadenine and compound C. CONCLUSIONS Repeated electroconvulsive seizure treatments activated in vivo autophagy in the rat frontal cortex through the AMPK signaling pathway.
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Affiliation(s)
- Se Hyun Kim
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyun Sook Yu
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Soyoung Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hong Geun Park
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yong Min Ahn
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ung Gu Kang
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Human Behavioral Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong Sik Kim
- Department of Psychiatry, Nowon Eulji Medical Center, Eulji University, Seoul, Republic of Korea
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AMP-activated protein kinase slows D2 dopamine autoreceptor desensitization in substantia nigra neurons. Neuropharmacology 2019; 158:107705. [PMID: 31301335 DOI: 10.1016/j.neuropharm.2019.107705] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 07/08/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022]
Abstract
Dopamine neurons in the substantia nigra zona compacta (SNC) are well known to express D2 receptors. When dopamine is released from somatodendritic sites, activation of D2 autoreceptors suppresses dopamine neuronal activity through activation of G protein-coupled K+ channels. AMP-activated protein kinase (AMPK) is a master enzyme that acts in somatic tissues to suppress energy expenditure and encourage energy production. We hypothesize that AMPK may also conserve energy in central neurons by reducing desensitization of D2 autoreceptors. We used whole-cell patch-clamp recordings to study the effects of AMPK activators and inhibitors on D2 autoreceptor-mediated current in SNC neurons in midbrain slices from rat pups (11-23 days post-natal). Slices were superfused with 100 μM dopamine or 30 μM quinpirole for 25 min, which evoked outward currents that decayed slowly over time. Although the AMPK activators A769662 and ZLN024 significantly slowed rundown of dopamine-evoked current, slowing of quinpirole-evoked current required the presence of a D1-like agonist (SKF38393). Moreover, the D1-like agonist also slowed the rundown of quinpirole-induced current even in the absence of an AMPK activator. Pharmacological antagonist experiments showed that the D1-like agonist effect required activation of either protein kinase A (PKA) or exchange protein directly activated by cAMP 2 (Epac2) pathways. In contrast, the effect of AMPK on rundown of current evoked by quinpirole plus SKF38393 required PKA but not Epac2. We conclude that AMPK slows D2 autoreceptor desensitization by augmenting the effect of D1-like receptors.
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Bentea E, Depasquale EA, O’Donovan SM, Sullivan CR, Simmons M, Meador-Woodruff JH, Zhou Y, Xu C, Bai B, Peng J, Song H, Ming GL, Meller J, Wen Z, McCullumsmith RE. Kinase network dysregulation in a human induced pluripotent stem cell model of DISC1 schizophrenia. Mol Omics 2019; 15:173-188. [PMID: 31106784 PMCID: PMC6563817 DOI: 10.1039/c8mo00173a] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Protein kinases orchestrate signal transduction pathways involved in central nervous system functions ranging from neurodevelopment to synaptic transmission and plasticity. Abnormalities in kinase-mediated signaling are involved in the pathophysiology of neurological disorders, including neuropsychiatric disorders. Here, we expand on the hypothesis that kinase networks are dysregulated in schizophrenia. We investigated changes in serine/threonine kinase activity in cortical excitatory neurons differentiated from induced pluripotent stem cells (iPSCs) from a schizophrenia patient presenting with a 4 bp mutation in the disrupted in schizophrenia 1 (DISC1) gene and a corresponding control. Using kinome peptide arrays, we demonstrate large scale abnormalities in DISC1 cells, including a global depression of serine/threonine kinase activity, and changes in activity of kinases, including AMP-activated protein kinase (AMPK), extracellular signal-regulated kinases (ERK), and thousand-and-one amino acid (TAO) kinases. Using isogenic cell lines in which the DISC1 mutation is either introduced in the control cell line, or rescued in the schizophrenia cell line, we ascribe most of these changes to a direct effect of the presence of the DISC1 mutation. Investigating the gene expression signatures downstream of the DISC1 kinase network, and mapping them on perturbagen signatures obtained from the Library of Integrated Network-based Cellular Signatures (LINCS) database, allowed us to propose novel drug targets able to reverse the DISC1 kinase dysregulation gene expression signature. Altogether, our findings provide new insight into abnormalities of kinase networks in schizophrenia and suggest possible targets for disease intervention.
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Affiliation(s)
- Eduard Bentea
- Center for Neurosciences (C4N), Department of Pharmaceutical Biotechnology and Molecular Biology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Erica A.K. Depasquale
- Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Sinead M. O’Donovan
- Department of Neurosciences, University of Toledo College of Medicine, Toledo, OH, USA
| | | | - Micah Simmons
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - James H. Meador-Woodruff
- Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ying Zhou
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Chongchong Xu
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA
| | - Bing Bai
- Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, P. R. China
| | - Junmin Peng
- Departments of Structural Biology and Developmental Neurobiology, Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guo-li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104, USA
- Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Jarek Meller
- Department of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Departments of Environmental Health, Electrical Engineering & Computing Systems and Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Zhexing Wen
- Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Neurology, Emory University School of Medicine, Atlanta, GA, USA
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Fan J, Li D, Chen HS, Huang JG, Xu JF, Zhu WW, Chen JG, Wang F. Metformin produces anxiolytic-like effects in rats by facilitating GABA A receptor trafficking to membrane. Br J Pharmacol 2018; 176:297-316. [PMID: 30318707 DOI: 10.1111/bph.14519] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 09/15/2018] [Accepted: 09/19/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND AND PURPOSE Altered function or expression of GABAA receptors contributes to anxiety disorders. Benzodiazepines are widely prescribed for the treatment of anxiety. However, the long-term use of benzodiazepines increases the risk of developing drug dependence and tolerance. Thus, it is urgent to explore new therapeutic approaches. Metformin is widely used to treat Type 2 diabetes and other metabolic syndromes. However, the role of metformin in psychiatric disorders, especially anxiety, remains largely unknown. EXPERIMENTAL APPROACH We examined the effects of metformin on anxiety-like behaviour of rats in open field test and elevated plus maze test. We also observed the effect of metformin (10 μM, in vitro; 100 mg·kg-1 , in vivo) on the trafficking of GABAA receptors, as mechanisms underlying the anxiolytic effects of metformin. KEY RESULTS Metformin (100 mg·kg-1 , i.p. 30 min) displayed a robust and rapid anxiolytic effect, without tolerance. Metformin up-regulated the surface expression of GABAA receptors and increased miniature inhibitory postsynaptic currents (mIPSCs). AMP-activated protein kinase (AMPK) activated by metformin-induced stimulation of forkhead box O3a (FoxO3a) transcriptional activity, followed by increased expression of GABAA receptor-associated protein (GABARAP) and its binding to GABAA receptors finally resulted in the membrane insertion of GABAA receptors. CONCLUSIONS AND IMPLICATIONS Metformin increased mIPSCs by up-regulating the membrane insertion of GABAA receptors, via a pathway involving AMPK, FoxO3a, and the GABAA receptor-associated protein. Thus metformin has a potential new use in the treatment of anxiety disorders.
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Affiliation(s)
- Jun Fan
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Di Li
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hong-Sheng Chen
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Geng Huang
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun-Feng Xu
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wen-Wen Zhu
- Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jian-Guo Chen
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China.,Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (HUST), Wuhan, China.,Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China.,The Collaborative-Innovation Center for Brain Science, Wuhan, China
| | - Fang Wang
- Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China.,Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (HUST), Wuhan, China.,Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China.,The Collaborative-Innovation Center for Brain Science, Wuhan, China
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Jiang S, Li T, Ji T, Yi W, Yang Z, Wang S, Yang Y, Gu C. AMPK: Potential Therapeutic Target for Ischemic Stroke. Theranostics 2018; 8:4535-4551. [PMID: 30214637 PMCID: PMC6134933 DOI: 10.7150/thno.25674] [Citation(s) in RCA: 180] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 07/16/2018] [Indexed: 02/07/2023] Open
Abstract
5'-AMP-activated protein kinase (AMPK), a member of the serine/threonine (Ser/Thr) kinase group, is universally distributed in various cells and organs. It is a significant endogenous defensive molecule that responds to harmful stimuli, such as cerebral ischemia, cerebral hemorrhage, and, neurodegenerative diseases (NDD). Cerebral ischemia, which results from insufficient blood flow or the blockage of blood vessels, is a major cause of ischemic stroke. Ischemic stroke has received increased attention due to its '3H' effects, namely high mortality, high morbidity, and high disability. Numerous studies have revealed that activation of AMPK plays a protective role in the brain, whereas its action in ischemic stroke remains elusive and poorly understood. Based on existing evidence, we introduce the basic structure, upstream regulators, and biological roles of AMPK. Second, we analyze the relationship between AMPK and the neurovascular unit (NVU). Third, the actions of AMPK in different phases of ischemia and current therapeutic methods are discussed. Finally, we evaluate existing controversy and provide a detailed analysis, followed by ethical issues, potential directions, and further prospects of AMPK. The information complied here may aid in clinical and basic research of AMPK, which may be a potent drug candidate for ischemic stroke treatment in the future.
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Affiliation(s)
- Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China
- Department of Aerospace Medicine, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Tian Li
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Ting Ji
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China
| | - Wei Yi
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
| | - Zhi Yang
- Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi'an 710032, China
| | - Simeng Wang
- Center for Human Nutrition, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education. Faculty of Life Sciences, Northwest University, 229 Taibai North Road, Xi'an 710069, China
| | - Chunhu Gu
- Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi'an 710032, China
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Orts-Del'Immagine A, Pugh JR. Activity-dependent plasticity of presynaptic GABA B receptors at parallel fiber synapses. Synapse 2018; 72:e22027. [PMID: 29360168 DOI: 10.1002/syn.22027] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 01/05/2018] [Accepted: 01/21/2018] [Indexed: 01/10/2023]
Abstract
Parallel fiber synapses in the cerebellum express a wide range of presynaptic receptors. However, presynaptic receptor expression at individual parallel fiber synapses is quite heterogeneous, suggesting physiological mechanisms regulate presynaptic receptor expression. We investigated changes in presynaptic GABAB receptors at parallel fiber-stellate cell synapses in acute cerebellar slices from juvenile mice. GABAB receptor-mediated inhibition of excitatory postsynaptic currents (EPSCs) is remarkably diverse at these synapses, with transmitter release at some synapses inhibited by >50% and little or no inhibition at others. GABAB receptor-mediated inhibition was significantly reduced following 4 Hz parallel fiber stimulation but not after stimulation at other frequencies. The reduction in GABAB receptor-mediated inhibition was replicated by bath application of forskolin and blocked by application of a PKA inhibitor, suggesting activation of adenylyl cyclase and PKA are required. Immunolabeling for an extracellular domain of the GABAB2 subunit revealed reduced surface expression in the molecular layer after exposure to forskolin. GABAB receptor-mediated inhibition of action potential evoked calcium transients in parallel fiber varicosities was also reduced following bath application of forskolin, confirming presynaptic receptors are responsible for the reduced EPSC inhibition. These data demonstrate that presynaptic GABAB receptor expression can be a plastic property of synapses, which may compliment other forms of synaptic plasticity. This opens the door to novel forms of receptor plasticity previously confined primarily to postsynaptic receptors.
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Affiliation(s)
- Adeline Orts-Del'Immagine
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229
| | - Jason R Pugh
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78229
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Curry DW, Stutz B, Andrews ZB, Elsworth JD. Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson's Disease. JOURNAL OF PARKINSON'S DISEASE 2018; 8:161-181. [PMID: 29614701 PMCID: PMC6004921 DOI: 10.3233/jpd-171296] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular α-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD.
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Affiliation(s)
- Daniel W Curry
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Bernardo Stutz
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Zane B Andrews
- Department of Physiology, Monash University, Melbourne, VIC, Australia
- Monash Biomedicine Discovery Institute, Monash University, VIC, Australia
| | - John D Elsworth
- Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA
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TERUNUMA M. Diversity of structure and function of GABA B receptors: a complexity of GABA B-mediated signaling. PROCEEDINGS OF THE JAPAN ACADEMY. SERIES B, PHYSICAL AND BIOLOGICAL SCIENCES 2018; 94:390-411. [PMID: 30541966 PMCID: PMC6374141 DOI: 10.2183/pjab.94.026] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Accepted: 10/09/2018] [Indexed: 05/24/2023]
Abstract
γ-aminobutyric acid type B (GABAB) receptors are broadly expressed in the nervous system and play an important role in neuronal excitability. GABAB receptors are G protein-coupled receptors that mediate slow and prolonged inhibitory action, via activation of Gαi/o-type proteins. GABAB receptors mediate their inhibitory action through activating inwardly rectifying K+ channels, inactivating voltage-gated Ca2+ channels, and inhibiting adenylate cyclase. Functional GABAB receptors are obligate heterodimers formed by the co-assembly of R1 and R2 subunits. It is well established that GABAB receptors interact not only with G proteins and effectors but also with various proteins. This review summarizes the structure, subunit isoforms, and function of GABAB receptors, and discusses the complexity of GABAB receptors, including how receptors are localized in specific subcellular compartments, the mechanism regulating cell surface expression and mobility of the receptors, and the diversity of receptor signaling through receptor crosstalk and interacting proteins.
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Affiliation(s)
- Miho TERUNUMA
- Division of Oral Biochemistry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
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40
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Price TJ, Das V, Dussor G. Adenosine Monophosphate-activated Protein Kinase (AMPK) Activators For the Prevention, Treatment and Potential Reversal of Pathological Pain. Curr Drug Targets 2017; 17:908-20. [PMID: 26521775 DOI: 10.2174/1389450116666151102095046] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 10/20/2015] [Accepted: 10/29/2015] [Indexed: 12/23/2022]
Abstract
Pathological pain is an enormous medical problem that places a significant burden on patients and can result from an injury that has long since healed or be due to an unidentifiable cause. Although treatments exist, they often either lack efficacy or have intolerable side effects. More importantly, they do not reverse the changes in the nervous system mediating pathological pain, and thus symptoms often return when therapies are discontinued. Consequently, novel therapies are urgently needed that have both improved efficacy and disease-modifying properties. Here we highlight an emerging target for novel pain therapies, adenosine monophosphate-activated protein kinase (AMPK). AMPK is capable of regulating a variety of cellular processes including protein translation, activity of other kinases, and mitochondrial metabolism, many of which are thought to contribute to pathological pain. Consistent with these properties, preclinical studies show positive, and in some cases disease-modifying effects of either pharmacological activation or genetic regulation of AMPK in models of nerve injury, chemotherapy-induced peripheral neuropathy (CIPN), postsurgical pain, inflammatory pain, and diabetic neuropathy. Given the AMPK-activating ability of metformin, a widely prescribed and well-tolerated drug, these preclinical studies provide a strong rationale for both retrospective and prospective human pain trials with this drug. They also argue for the development of novel AMPK activators, whether orthosteric, allosteric, or modulators of events upstream of the kinase. Together, this review will present the case for AMPK as a novel therapeutic target for pain and will discuss future challenges in the path toward development of AMPK-based pain therapeutics.
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Affiliation(s)
- Theodore J Price
- School of Behavioral and Brain Sciences, University of Texas at Dallas, JO 4.212 800 W Campbell Rd, Richardson TX 75080, USA.
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41
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Zhang R, Lin YQ, Wang WS, Wang XQ. Excessive nNOS/NO/AMPK signaling activation mediated by the blockage of the CBS/H2S system contributes to oxygen‑glucose deprivation‑induced endoplasmic reticulum stress in PC12 cells. Int J Mol Med 2017; 40:549-557. [PMID: 28656194 DOI: 10.3892/ijmm.2017.3035] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 05/25/2017] [Indexed: 11/06/2022] Open
Abstract
Hypoxic‑ischemia stress causes severe brain injury, leading to death and disability worldwide. Although it has been reported that endoplasmic reticulum (ER) stress is an essential step in the progression of hypoxia or ischemia‑induced brain injury, the underlying molecular mechanisms are and have not yet been fully elucidated. Accumulating evidence has indicated that both nitric oxide (NO) and hydrogen sulfide (H2S) play an important role in the development of cerebral ischemic injury. In the present study, we aimed to investigate the effect of the association between NO signaling and the cystathionine β‑synthase (CBS)/H2S system on ER stress in a cell model of cerebral hypoxia‑ischemia injury. We found that oxygen‑glucose deprivation (OGD) markedly increased the NO level and neuronal NO synthase (nNOS) activity. 3‑Bromo‑7‑nitroindazole (3‑Br‑7‑NI), a relatively selective nNOS inhibitor, abolished the OGD‑induced inhibition of cell viability and the increased expression of ER stress‑related proteins, including glucose‑regulated protein 78 (GRP78), C/EBP homologous protein (CHOP) and cleaved caspase‑12 in PC12 cells, indicating the contribution of excessive nNOS/NO signaling to OGD‑induced ER stress. Furthermore, we found that OGD increased the phosphorylated AMP‑activated protein kinase (p‑AMPK)/AMPK ratio, and the AMPK activator, 5‑aminoimidazole‑4‑carboxamide‑1‑β‑D‑ribofuranoside (AICAR), attenuated the effects on OGD‑induced ER stress, suggesting that OGD‑induced NO overproduction results in AMPK activation in PC12 cells. We also found that OGD induced the downregulation of the CBS/H2S system, as indicated by the decreased H2S level in the culture supernatant and CBS activity in PC12 cells. In addition, we found that treatment with NaHS (a H2S donor) or S‑adenosyl‑L‑methionine (SAM, a CBS agonist) mitigated OGD‑induced ER stress, as well as the NO level, nNOS activity and AMPK phosphorylation in PC12 cells. On the whole, these results suggest that the inhibition of the CBS/H2S system, which facilitated excessive nNOS/NO/AMPK activation, contributes to OGD‑induced ER stress.
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Affiliation(s)
- Rui Zhang
- Department of Neurology, Liaocheng People's Hospital, Liaocheng, Shandong 252000, P.R. China
| | - Yong-Quan Lin
- Department of Emergency Medicine, Yidu Central Hospital of Weifang, Qingzhou, Shandong 262500, P.R. China
| | - Wei-Sheng Wang
- Department of Neurology, The Third People's Hospital of Liaocheng City, Liaocheng, Shandong 252000, P.R. China
| | - Xin-Qiang Wang
- Department of Neurology, The Second People's Hospital of Liaocheng City, Linqing, Shandong 252601, P.R. China
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Arbeláez-Quintero I, Palacios M. To Use or Not to Use Metformin in Cerebral Ischemia: A Review of the Application of Metformin in Stroke Rodents. Stroke Res Treat 2017; 2017:9756429. [PMID: 28634570 PMCID: PMC5467394 DOI: 10.1155/2017/9756429] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 10/22/2016] [Accepted: 10/26/2016] [Indexed: 12/11/2022] Open
Abstract
Ischemic strokes are major causes of death and disability. Searching for potential therapeutic strategies to prevent and treat stroke is necessary, given the increase in overall life expectancy. Epidemiological reports indicate that metformin is an oral antidiabetic medication that can reduce the incidence of ischemic events in patients with diabetes mellitus. Its mechanism of action has not been elucidated, but metformin pleiotropic effects involve actions in addition to glycemic control. AMPK activation has been described as one of the pharmacological mechanisms that explain the action of metformin and that lead to neuroprotective effects. Most experiments done in the cerebral ischemia model, via middle cerebral artery occlusion in rodents (MCAO), had positive results favoring metformin's neuroprotective role and involve several cellular pathways like oxidative stress, endothelial nitric oxide synthase activation, activation of angiogenesis and neurogenesis, autophagia, and apoptosis. We will review the pharmacological properties of metformin and its possible mechanisms that lead to neuroprotection in cerebral ischemia.
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Affiliation(s)
| | - Mauricio Palacios
- Centro de Estudios Cerebrales, Facultad de Salud, Universidad del Valle, Cali, Colombia
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43
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Gao XJ, Yuan K, Cao L, Yan W, Luo YX, Jian M, Liu JF, Fang Q, Wang JS, Han Y, Shi J, Lu L. AMPK signaling in the nucleus accumbens core mediates cue-induced reinstatement of cocaine seeking. Sci Rep 2017; 7:1038. [PMID: 28432301 PMCID: PMC5430902 DOI: 10.1038/s41598-017-01043-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 03/22/2017] [Indexed: 12/21/2022] Open
Abstract
Relapse to drug seeking can be caused by exposure to drug-associated cues, provoking drug craving even after prolonged abstinence. Recent studies demonstrated that AMP-activated protein kinase (AMPK) regulates neuronal morphology and membrane excitability in neurons. Here, we investigated the role of AMPK activity in the nucleus accumbens (NAc) in relapse to cocaine seeking. We found that exposure to drug-related cues reinstated cocaine-seeking behavior and increased AMPK and p70s6k phosphorylation in the NAc core but not shell. Augmenting AMPK activity by intra-NAc core infusions of the AMPK activator 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) or adenovirus expressing constitutively active subunits of AMPK decreased cue-induced reinstatement of cocaine seeking and inhibited the mammalian target of rapamycin complex 1 (mTORC1) and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways. In contrast, inhibition of AMPK activity by intra-NAc core infusions of the AMPK inhibitor compound C or adenovirus expressing dominant-negative subunits of AMPK increased cue-induced reinstatement of cocaine seeking and enhanced mTORC1 and ERK1/2 activity. The regulation of AMPK activity in the NAc shell had no effect on cue-induced cocaine seeking. Altogether, these results indicate that AMPK activity in the NAc core is critical for the cue-induced reinstatement of cocaine seeking, which may be mediated by mTORC1 and ERK1/2 signaling.
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Affiliation(s)
- Xue-Jiao Gao
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.,Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.,Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China
| | - Kai Yuan
- Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China.,Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China
| | - Lu Cao
- Affiliated Hospital and School of Pharmacy of Guizhou Medical University, Guiyang, China
| | - Wei Yan
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.,Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Yi-Xiao Luo
- Department of Pharmacy, Medical College, Hunan Normal University, Changsha, China
| | - Min Jian
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China
| | - Jian-Feng Liu
- Department of Pharmacology and Toxicology, University at Buffalo, State University of New York, Buffalo, NY, USA
| | - Qin Fang
- Affiliated Hospital and School of Pharmacy of Guizhou Medical University, Guiyang, China
| | - Ji-Shi Wang
- Affiliated Hospital and School of Pharmacy of Guizhou Medical University, Guiyang, China
| | - Ying Han
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China. .,Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
| | - Jie Shi
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China.
| | - Lin Lu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, China. .,Peking University Sixth Hospital, Peking University Institute of Mental Health, Key Laboratory of Mental Health, Ministry of Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China. .,Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
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44
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Kang JY, Chadchankar J, Vien TN, Mighdoll MI, Hyde TM, Mather RJ, Deeb TZ, Pangalos MN, Brandon NJ, Dunlop J, Moss SJ. Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome. J Biol Chem 2017; 292:6621-6632. [PMID: 28213518 PMCID: PMC5399111 DOI: 10.1074/jbc.m116.772541] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2016] [Revised: 02/07/2017] [Indexed: 11/06/2022] Open
Abstract
The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABAB) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of Gi/o, they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABAB receptors (GABABRs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABABRs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABABRs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABABRs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABABR agonist (R)-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABABRs contribute to the pathophysiology of FXS.
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Affiliation(s)
- Ji-Yong Kang
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Jayashree Chadchankar
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Thuy N Vien
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | | | - Thomas M Hyde
- the Lieber Institute for Brain Development and
- Departments of Neurology and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205
| | - Robert J Mather
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
- Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451
| | - Tarek Z Deeb
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
| | - Menelas N Pangalos
- Innovative Medicines and Early Development, AstraZeneca, Melbourn Science Park, Cambridge Road, Royston Herts SG8 6EE, United Kingdom, and
| | - Nicholas J Brandon
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
- Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451
| | - John Dunlop
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
- Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451
| | - Stephen J Moss
- From the AstraZeneca Tufts Laboratory for Basic and Translational Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111,
- Neuroscience, Innovative Medicines and Early Development, AstraZeneca, Waltham, Massachusetts 02451
- the Department of Neuroscience, Physiology and Pharmacology, University College, London WC1E 6BT, United Kingdom
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45
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Pineda-Ramírez N, Gutiérrez Aguilar GF, Espinoza-Rojo M, Aguilera P. Current evidence for AMPK activation involvement on resveratrol-induced neuroprotection in cerebral ischemia. Nutr Neurosci 2017; 21:229-247. [DOI: 10.1080/1028415x.2017.1284361] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Narayana Pineda-Ramírez
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía ‘Manuel Velasco Suárez’, Ciudad de México, 14269, México
| | - Germán Fernando Gutiérrez Aguilar
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía ‘Manuel Velasco Suárez’, Ciudad de México, 14269, México
| | - Mónica Espinoza-Rojo
- Laboratorio de Biología Molecular y Genómica, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, 39087, México
| | - Penélope Aguilera
- Laboratorio de Patología Vascular Cerebral, Instituto Nacional de Neurología y Neurocirugía ‘Manuel Velasco Suárez’, Ciudad de México, 14269, México
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46
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Hong Z, Tian Y, Qi M, Li Y, Du Y, Chen L, Liu W, Chen L. Transient Receptor Potential Vanilloid 4 Inhibits γ-Aminobutyric Acid-Activated Current in Hippocampal Pyramidal Neurons. Front Mol Neurosci 2016; 9:77. [PMID: 27616980 PMCID: PMC4999446 DOI: 10.3389/fnmol.2016.00077] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 08/10/2016] [Indexed: 12/26/2022] Open
Abstract
The balance between excitatory and inhibitory neurotransmitter systems is crucial for the modulation of neuronal excitability in the central nervous system (CNS). The activation of transient receptor potential vanilloid 4 (TRPV4) is reported to enhance the response of hippocampal glutamate receptors, but whether the inhibitory neurotransmitter system can be regulated by TRPV4 remains unknown. γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. Here, we show that application of transient receptor potential vanilloid 4 (TRPV4) synthetic (GSK1016790A or 4α-PDD) or endogenous agonist (5,6-EET) inhibited GABA-activated current (IGABA) in hippocampal CA1 pyramidal neurons, which was blocked by specific antagonists of TRPV4 and of GABAA receptors. GSK1016790A increased the phosphorylated AMP-activated protein kinase (p-AMPK) and decreased the phosphorylated protein kinase B (p-Akt) protein levels, which was attenuated by removing extracellular calcium or by a calcium/calmodulin-dependent protein kinase kinase-β antagonist. GSK1016790A-induced decrease of p-Akt protein level was sensitive to an AMPK antagonist. GSK1016790A-inhibited IGABA was blocked by an AMPK antagonist or a phosphatidyl inositol 3 kinase (PI3K) agonist. GSK1016790A-induced inhibition of IGABA was also significantly attenuated by a protein kinase C (PKC) antagonist but was unaffected by protein kinase A or calcium/calmodulin-dependent protein kinase II antagonist. We conclude that activation of TRPV4 inhibits GABAA receptor, which may be mediated by activation of AMPK and subsequent down-regulation of PI3K/Akt signaling and activation of PKC signaling. Inhibition of GABAA receptors may account for the neuronal hyperexcitability caused by TRPV4 activation.
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Affiliation(s)
- Zhiwen Hong
- Department of Physiology, Nanjing Medical University Nanjing, China
| | - Yujing Tian
- Department of Physiology, Nanjing Medical University Nanjing, China
| | - Mengwen Qi
- Department of Physiology, Nanjing Medical University Nanjing, China
| | - Yingchun Li
- Department of Physiology, Nanjing Medical University Nanjing, China
| | - Yimei Du
- Research Center of Ion Channelopathy, Institute of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Lei Chen
- Department of Physiology, Nanjing Medical University Nanjing, China
| | - Wentao Liu
- Department of Pharmacology, Nanjing Medical University Nanjing, China
| | - Ling Chen
- Department of Physiology, Nanjing Medical University Nanjing, China
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47
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Hannan S, Gerrow K, Triller A, Smart TG. Phospho-dependent Accumulation of GABABRs at Presynaptic Terminals after NMDAR Activation. Cell Rep 2016; 16:1962-73. [PMID: 27498877 PMCID: PMC4987283 DOI: 10.1016/j.celrep.2016.07.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 04/19/2016] [Accepted: 07/09/2016] [Indexed: 11/24/2022] Open
Abstract
Here, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca(2+)-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity.
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Affiliation(s)
- Saad Hannan
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK
| | - Kim Gerrow
- Biologie Cellulaire de la Synapse, Inserm U1024, Institute of Biology, École Normale Supérieure (ENS), 46 rue d'Ulm, Paris 75005, France
| | - Antoine Triller
- Biologie Cellulaire de la Synapse, Inserm U1024, Institute of Biology, École Normale Supérieure (ENS), 46 rue d'Ulm, Paris 75005, France
| | - Trevor G Smart
- Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.
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48
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Otth C, Leyton L, Salamin M, Acuña-Hinrichsen F, Martin C, Concha MI. Herpes Simplex Virus Type 1 Neuronal Infection Elicits Cellular and Molecular Mechanisms of Neuroinflammation and Neurodegeneration in in vitro and in vivo Mice Models. J Alzheimers Dis 2016. [DOI: 10.3233/jad-160508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Carola Otth
- Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Luis Leyton
- Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Marukel Salamin
- Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Francisca Acuña-Hinrichsen
- Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
- Centro Interdisciplinario de Estudios del Sistema Nervioso (CISNe), Universidad Austral de Chile, Valdivia, Chile
| | - Carolina Martin
- Instituto de Microbiología Clínica, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Margarita I. Concha
- Instituto de Bioquimica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
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49
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Shen KZ, Wu YN, Munhall AC, Johnson SW. AMP kinase regulates ligand-gated K-ATP channels in substantia nigra dopamine neurons. Neuroscience 2016; 330:219-28. [PMID: 27267246 DOI: 10.1016/j.neuroscience.2016.06.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 05/31/2016] [Accepted: 06/01/2016] [Indexed: 12/29/2022]
Abstract
AMP-activated protein kinase (AMPK) is a master enzyme that regulates ATP-sensitive K(+) (K-ATP) channels in pancreatic beta-cells and cardiac myocytes. We used patch pipettes to record currents and potentials to investigate effects of AMPK on K-ATP currents in substantia nigra compacta (SNC) dopamine neurons in slices of rat midbrain. When slices were superfused repeatedly with the K-ATP channel opener diazoxide, we were surprised to find that diazoxide currents gradually increased in magnitude, reaching 300% of the control value 60min after starting whole-cell recording. However, diazoxide current increased significantly more, to 472% of control, when recorded in the presence of the AMPK activator A769662. Moreover, superfusing the slice with the AMPK blocking agent dorsomorphin significantly reduced diazoxide current to 38% of control. Control experiments showed that outward currents evoked by the K-ATP channel opener NN-414 also increased over time, but not currents evoked by the GABAB agonist baclofen. Delaying the application of diazoxide after starting whole-cell recording correlated with augmentation of current. Loose-patch recording showed that diazoxide produced a 34% slowing of spontaneous firing rate that did not intensify with repeated applications of diazoxide. However, superfusion with A769662 significantly augmented the inhibitory effect of diazoxide on firing rate. We conclude that K-ATP channel function is augmented by AMPK, which is activated during the process of making whole-cell recordings. Our results suggest that AMPK and K-ATP interactions may play an important role in regulating dopamine neuronal excitability.
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Affiliation(s)
- Ke-Zhong Shen
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Yan-Na Wu
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA
| | - Adam C Munhall
- Veterans Affairs Portland Health Care System, Portland, OR 97239, USA
| | - Steven W Johnson
- Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA; Veterans Affairs Portland Health Care System, Portland, OR 97239, USA.
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50
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Suski M, Olszanecki R, Chmura Ł, Stachowicz A, Madej J, Okoń K, Adamek D, Korbut R. Influence of metformin on mitochondrial subproteome in the brain of apoE knockout mice. Eur J Pharmacol 2016; 772:99-107. [DOI: 10.1016/j.ejphar.2015.12.036] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2015] [Revised: 12/17/2015] [Accepted: 12/18/2015] [Indexed: 01/08/2023]
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