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Jenkins PM, Bender KJ. Axon initial segment structure and function in health and disease. Physiol Rev 2025; 105:765-801. [PMID: 39480263 DOI: 10.1152/physrev.00030.2024] [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: 08/01/2024] [Revised: 10/18/2024] [Accepted: 10/23/2024] [Indexed: 11/06/2024] Open
Abstract
At the simplest level, neurons are structured to integrate synaptic input and perform computational transforms on that input, converting it into an action potential (AP) code. This process, converting synaptic input into AP output, typically occurs in a specialized region of the axon termed the axon initial segment (AIS). The AIS, as its name implies, is often contained to the first section of axon abutted to the soma and is home to a dizzying array of ion channels, attendant scaffolding proteins, intracellular organelles, extracellular proteins, and, in some cases, synapses. The AIS serves multiple roles as the final arbiter for determining if inputs are sufficient to evoke APs, as a gatekeeper that physically separates the somatodendritic domain from the axon proper, and as a regulator of overall neuronal excitability, dynamically tuning its size to best suit the needs of parent neurons. These complex roles have received considerable attention from experimentalists and theoreticians alike. Here, we review recent advances in our understanding of the AIS and its role in neuronal integration and polarity in health and disease.
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Affiliation(s)
- Paul M Jenkins
- Departments of Pharmacology and Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan, United States
| | - Kevin J Bender
- Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, California, United States
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Qebibo L, Davakan A, Nesson-Dauphin M, Boulali N, Siquier-Pernet K, Afenjar A, Amiel J, Bartholdi D, Barth M, Blondiaux E, Cristian I, Frazier Z, Goldenberg A, Good JM, Salussolia CL, Sahin M, McCullagh H, McDonald K, McRae A, Morrison J, Pinner J, Shinawi M, Toutain A, Vyhnálková E, Wheeler PG, Wilnai Y, Hausman-Kedem M, Coolen M, Cantagrel V, Burglen L, Lory P. The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND. Genet Med 2025; 27:101337. [PMID: 39674904 DOI: 10.1016/j.gim.2024.101337] [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: 08/07/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 12/17/2024] Open
Abstract
PURPOSE Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND. METHODS We describe 19 patients with congenital CACNA1G-variants, including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants, including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity. RESULTS We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics and an increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity. CONCLUSION This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.
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Affiliation(s)
- Leila Qebibo
- Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, AP-HP. Sorbonne Université, Paris, France; Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France
| | - Amaël Davakan
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx "Ion Channel Science and Therapeutics," Montpellier, France
| | - Mathilde Nesson-Dauphin
- Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France
| | - Najlae Boulali
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx "Ion Channel Science and Therapeutics," Montpellier, France
| | - Karine Siquier-Pernet
- Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France
| | - Alexandra Afenjar
- Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France
| | - Jeanne Amiel
- Service de Médecine Génomique des Maladies Rares, Necker Enfants Malades University Hospital, APHP, Paris, France
| | - Deborah Bartholdi
- Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Switzerland
| | - Magalie Barth
- Department of Biochemistry and Genetics, Angers University Hospital, Angers France
| | - Eléonore Blondiaux
- Department of Radiology, Armand-Trousseau Hospital, APHP, Sorbonne University, Paris, France
| | | | - Zoe Frazier
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Alice Goldenberg
- Université Rouen Normandie, INSERM U1245, CHU de Rouen, Department of Genetics and Reference Center for Developmental Disorders, Rouen, France
| | - Jean-Marc Good
- Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
| | - Catherine Lourdes Salussolia
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | - Mustafa Sahin
- Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA
| | | | - Kimberly McDonald
- Department of Pediatrics, University of Louisville, Norton Children's Hospital, Louisville, KY
| | - Anne McRae
- Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | | | - Jason Pinner
- Centre for Clinical Genetics, Sydney Children's Hospitals Network and University of New South Wales, Sydney, Australia
| | - Marwan Shinawi
- Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO
| | - Annick Toutain
- Unité fonctionnelle de Génétique Médicale, Centre Hospitalier Universitaire, Tours, France
| | - Emílie Vyhnálková
- Charles University, Motol University Hospital, Prague, Czech Republic
| | | | - Yael Wilnai
- Tel Aviv Sourasky Medical Center, Genetic Institute, Tel Aviv, Israel
| | - Moran Hausman-Kedem
- Pediatric Neurology Institute, Dana-Dwek Children's Hospital, Tel Aviv Medical Center and Faculty of Medical and Health Science, Tel-Aviv University, Tel-Aviv, Israel
| | - Marion Coolen
- Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France
| | - Vincent Cantagrel
- Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France.
| | - Lydie Burglen
- Pediatric Neurogenetics Laboratory, Department of Genetics, Armand-Trousseau Hospital, AP-HP. Sorbonne Université, Paris, France; Reference Center for Cerebellar Malformations and Congenital Diseases, Armand-Trousseau Hospital, APHP. Sorbonne Université, Paris, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Developmental Brain Disorders Laboratory, Paris, France.
| | - Philippe Lory
- IGF, Université de Montpellier, CNRS, INSERM, Montpellier, France; LabEx "Ion Channel Science and Therapeutics," Montpellier, France.
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Zadorozny L, Du J, Supanekar N, Annamalai K, Yu Q, Wang M. Caveolin and oxidative stress in cardiac pathology. Front Physiol 2025; 16:1550647. [PMID: 40041164 PMCID: PMC11876135 DOI: 10.3389/fphys.2025.1550647] [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: 12/23/2024] [Accepted: 01/27/2025] [Indexed: 03/06/2025] Open
Abstract
Caveolins interact with signaling molecules within caveolae and subcellular membranes. Dysregulation of caveolin function and protein abundance contributes to cardiac pathophysiological processes, driving the development and progression of heart disease. Reactive oxygen species (ROS) play a critical role in maintaining cellular homeostasis and are key contributors to the pathophysiological mechanisms of cardiovascular disorders. Caveolins have been shown to modulate oxidative stress and regulate redox homeostasis. However, the specific roles of caveolins, particularly caveolin-1 and caveolin-3, in regulating ROS production during cardiac pathology remain unclear. This mini-review article highlights the correlation between caveolins and oxidative stress in maintaining cardiovascular health and modulating cardiac diseases, specifically in myocardial ischemia, heart failure, diabetes-induced metabolic cardiomyopathy, and septic cardiomyopathy. A deeper understanding of caveolin-mediated mechanisms may pave the way for innovative therapeutic approaches to treat cardiovascular diseases.
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Affiliation(s)
- Lauren Zadorozny
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Division of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Jiayue Du
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Division of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Neil Supanekar
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Karthik Annamalai
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Qing Yu
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Division of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Meijing Wang
- Center for Surgical Sciences, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
- Division of Cardiothoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
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Brenna A, Borsa M, Saro G, Ripperger JA, Glauser DA, Yang Z, Adamantidis A, Albrecht U. Cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and gates rapid phase shifts of the circadian clock. eLife 2025; 13:RP97029. [PMID: 39937180 PMCID: PMC11820109 DOI: 10.7554/elife.97029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
The circadian clock enables organisms to synchronize biochemical and physiological processes over a 24 hr period. Natural changes in lighting conditions, as well as artificial disruptions like jet lag or shift work, can advance or delay the clock phase to align physiology with the environment. Within the suprachiasmatic nucleus (SCN) of the hypothalamus, circadian timekeeping and resetting rely on both membrane depolarization and intracellular second-messenger signaling. Voltage-gated calcium channels (VGCCs) facilitate calcium influx in both processes, activating intracellular signaling pathways that trigger Period (Per) gene expression. However, the precise mechanism by which these processes are concertedly gated remains unknown. Our study in mice demonstrates that cyclin-dependent kinase 5 (Cdk5) activity is modulated by light and regulates phase shifts of the circadian clock. We observed that knocking down Cdk5 in the SCN of mice affects phase delays but not phase advances. This is linked to uncontrolled calcium influx into SCN neurons and an unregulated protein kinase A (PKA)-calcium/calmodulin-dependent kinase (CaMK)-cAMP response element-binding protein (CREB) signaling pathway. Consequently, genes such as Per1 are not induced by light in the SCN of Cdk5 knock-down mice. Our experiments identified Cdk5 as a crucial light-modulated kinase that influences rapid clock phase adaptation. This finding elucidates how light responsiveness and clock phase coordination adapt activity onset to seasonal changes, jet lag, and shift work.
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Affiliation(s)
- Andrea Brenna
- Department of Biology, University of FribourgFribourgSwitzerland
- Department of Endocrinology, Metabolism, and Cardiovascular System, Section of Medicine, University of FribourgFribourgSwitzerland
| | - Micaela Borsa
- Zentrum für Experimentelle Neurologie, Department of Neurology, Inselspital, Bern University Hospital, University of BernBernSwitzerland
- Department of Biomedical Research, University of BernBernSwitzerland
| | - Gabriella Saro
- Department of Biology, University of FribourgFribourgSwitzerland
| | | | | | - Zhihong Yang
- Department of Endocrinology, Metabolism, and Cardiovascular System, Section of Medicine, University of FribourgFribourgSwitzerland
| | - Antoine Adamantidis
- Zentrum für Experimentelle Neurologie, Department of Neurology, Inselspital, Bern University Hospital, University of BernBernSwitzerland
- Department of Biomedical Research, University of BernBernSwitzerland
| | - Urs Albrecht
- Department of Biology, University of FribourgFribourgSwitzerland
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Kim JI, Miura Y, Li MY, Revah O, Selvaraj S, Birey F, Meng X, Thete MV, Pavlov SD, Andersen J, Pașca AM, Porteus MH, Huguenard JR, Pașca SP. Human assembloids reveal the consequences of CACNA1G gene variants in the thalamocortical pathway. Neuron 2024; 112:4048-4059.e7. [PMID: 39419023 DOI: 10.1016/j.neuron.2024.09.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 08/15/2024] [Accepted: 09/19/2024] [Indexed: 10/19/2024]
Abstract
Abnormalities in thalamocortical crosstalk can lead to neuropsychiatric disorders. Variants in CACNA1G, which encodes the α1G subunit of the thalamus-enriched T-type calcium channel, are associated with absence seizures, intellectual disability, and schizophrenia, but the cellular and circuit consequences of these genetic variants in humans remain unknown. Here, we developed a human assembloid model of the thalamocortical pathway to dissect the contribution of genetic variants in T-type calcium channels. We discovered that the M1531V CACNA1G variant associated with seizures led to changes in T-type currents in thalamic neurons, as well as correlated hyperactivity of thalamic and cortical neurons in assembloids. By contrast, CACNA1G loss, which has been associated with risk of schizophrenia, resulted in abnormal thalamocortical connectivity that was related to both increased spontaneous thalamic activity and aberrant axonal projections. These results illustrate the utility of multi-cellular systems for interrogating human genetic disease risk variants at both cellular and circuit level.
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Affiliation(s)
- Ji-Il Kim
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Yuki Miura
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Min-Yin Li
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Omer Revah
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA; Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
| | - Sridhar Selvaraj
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Fikri Birey
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Xiangling Meng
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Mayuri Vijay Thete
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Sergey D Pavlov
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Jimena Andersen
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA
| | - Anca M Pașca
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - Matthew H Porteus
- Department of Pediatrics, Stanford University, Stanford, CA 94305, USA
| | - John R Huguenard
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA 94305, USA
| | - Sergiu P Pașca
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA; Stanford Brain Organogenesis, Wu Tsai Neuroscience Institute, Stanford, CA 94305, USA.
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Zhu Y, Gu L, Wang J, Han J, Gou J, Wu Z. DNA methylation profiling of CpG islands in trigeminal ganglion of rats with orofacial pain induced by experimental tooth movement. BMC Oral Health 2024; 24:1474. [PMID: 39633318 PMCID: PMC11619421 DOI: 10.1186/s12903-024-05269-4] [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: 06/05/2024] [Accepted: 11/27/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Tooth movement induced orofacial pain is the most cited negative effect during orthodontic treatment, while treatment options without side effects are limited. The differential expression of pain-related genes due to DNA methylation and demethylation is instrumental in pain. The purpose of the study was to evaluate the DNA methylation profiling of CpG islands (CGI) and CGI shores in promoter regions in trigeminal ganglions (TG) of tooth movement induced orofacial pain rats, thus to further insight the DNA methylation regulation in orofacial pain. MATERIALS AND METHODS An orofacial pain rat model was constructed by ligating coil springs between the incisor and first maxillary molar with 40 g of force. The Rat Grimace Score (RGS) was used for pain evaluation. The genome methylation status was analyzed by the reduced representation bisulfite sequencing (RRBS) technique. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analyses were conducted in the differentially methylated regions (DMRs). Moreover, a protein-protein interaction (PPI) network was established to detect annotated genes associated with pain. RESULTS RGS was significantly higher in orofacial pain rats than in sham rats. RRBS showed widespread methylation changes in CGI and CGI shores in TG promoter regions. Both 902 hypermethylated DMRs and 862 hypomethylated DMRs were found in the CGIs of promoter regions. KEGG analysis revealed that annotated genes are participated in endocrine, nervous, immune, and sensory systems. Moreover, the "Calcium signaling pathway", "Wnt signaling pathway" and "Neuroactive ligand-receptor interaction" were significantly enriched pathways. Furthermore, PPI network showed several genes (Ctnnb1, Dlg4, Creb1, Camk2g, Bmp2, etc.) with different methylation statuses were reported to be associated with pain. CONCLUSIONS This study demonstrated methylation changes were existed in CGI and CGI shores in TG promoter regions when pain occurs, thus providing a basis for further study on the mechanism of DNA methylation in orofacial pain.
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Affiliation(s)
- Yafen Zhu
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Liqun Gu
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Jian Wang
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Jie Han
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Junzhuo Gou
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China
| | - Zhifang Wu
- Department of Pediatric Dentistry, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, 310000, China.
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Onesto MM, Kim JI, Pasca SP. Assembloid models of cell-cell interaction to study tissue and disease biology. Cell Stem Cell 2024; 31:1563-1573. [PMID: 39454582 DOI: 10.1016/j.stem.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/26/2024] [Accepted: 09/23/2024] [Indexed: 10/28/2024]
Abstract
Neurodevelopment involves the migration, projection, and integration of various cell types across different regions of the nervous system. Assembloids are self-organizing systems formed by the integration of multiple organoids or cell types. Here, we outline the generation and application of assembloids. We illustrate how assembloids recapitulate critical neurodevelopmental steps, like migration, axon projection, and circuit formation, and how they are starting to provide biological insights into neuropsychiatric disorders. Additionally, we review how assembloids can be used to study properties emerging from cell-cell interactions within non-neural tissues. Overall, assembloid platforms represent a powerful tool for discovering human biology and developing therapeutics.
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Affiliation(s)
- Massimo M Onesto
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute and Bio-X, Stanford University, Stanford, CA, USA
| | - Ji-Il Kim
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute and Bio-X, Stanford University, Stanford, CA, USA
| | - Sergiu P Pasca
- Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA; Stanford Brain Organogenesis, Wu Tsai Neurosciences Institute and Bio-X, Stanford University, Stanford, CA, USA.
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Al-Beltagi M, Saeed NK, Bediwy AS, Bediwy EA, Elbeltagi R. Decoding the genetic landscape of autism: A comprehensive review. World J Clin Pediatr 2024; 13:98468. [PMID: 39350903 PMCID: PMC11438927 DOI: 10.5409/wjcp.v13.i3.98468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/30/2024] Open
Abstract
BACKGROUND Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by heterogeneous symptoms and genetic underpinnings. Recent advancements in genetic and epigenetic research have provided insights into the intricate mechanisms contributing to ASD, influencing both diagnosis and therapeutic strategies. AIM To explore the genetic architecture of ASD, elucidate mechanistic insights into genetic mutations, and examine gene-environment interactions. METHODS A comprehensive systematic review was conducted, integrating findings from studies on genetic variations, epigenetic mechanisms (such as DNA methylation and histone modifications), and emerging technologies [including Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 and single-cell RNA sequencing]. Relevant articles were identified through systematic searches of databases such as PubMed and Google Scholar. RESULTS Genetic studies have identified numerous risk genes and mutations associated with ASD, yet many cases remain unexplained by known factors, suggesting undiscovered genetic components. Mechanistic insights into how these genetic mutations impact neural development and brain connectivity are still evolving. Epigenetic modifications, particularly DNA methylation and non-coding RNAs, also play significant roles in ASD pathogenesis. Emerging technologies like CRISPR-Cas9 and advanced bioinformatics are advancing our understanding by enabling precise genetic editing and analysis of complex genomic data. CONCLUSION Continued research into the genetic and epigenetic underpinnings of ASD is crucial for developing personalized and effective treatments. Collaborative efforts integrating multidisciplinary expertise and international collaborations are essential to address the complexity of ASD and translate genetic discoveries into clinical practice. Addressing unresolved questions and ethical considerations surrounding genetic research will pave the way for improved diagnostic tools and targeted therapies, ultimately enhancing outcomes for individuals affected by ASD.
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Affiliation(s)
- Mohammed Al-Beltagi
- Department of Pediatric, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31511, Egypt
- Department of Pediatric, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Nermin Kamal Saeed
- Medical Microbiology Section, Department of Pathology, Salmaniya Medical Complex, Ministry of Health, Kingdom of Bahrain, Manama 12, Bahrain
- Medical Microbiology Section, Department of Pathology, Irish Royal College of Surgeon, Muharraq, Busaiteen 15503, Bahrain
| | - Adel Salah Bediwy
- Department of Pulmonology, Faculty of Medicine, Tanta University, Alghrabia, Tanta 31527, Egypt
- Department of Pulmonology, University Medical Center, King Abdulla Medical City, Arabian Gulf University, Manama 26671, Bahrain
| | - Eman A Bediwy
- Internal Medicine, Faculty of Medicine, Tanta University, Algharbia, Tanta 31527, Egypt
| | - Reem Elbeltagi
- Department of Medicine, The Royal College of Surgeons in Ireland-Bahrain, Muharraq, Busiateen 15503, Bahrain
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Abdelaal MS, Kato T, Natsubori A, Tanaka KF. Temporal and Potential Predictive Relationships between Sleep Spindle Density and Spike-and-Wave Discharges. eNeuro 2024; 11:ENEURO.0058-24.2024. [PMID: 39256042 PMCID: PMC11412100 DOI: 10.1523/eneuro.0058-24.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 08/27/2024] [Accepted: 08/29/2024] [Indexed: 09/12/2024] Open
Abstract
Spike-and-wave discharges (SWDs) and sleep spindles are characteristic electroencephalographic (EEG) hallmarks of absence seizures and nonrapid eye movement sleep, respectively. They are commonly generated by the cortico-thalamo-cortical network including the thalamic reticular nucleus (TRN). It has been reported that SWD development is accompanied by a decrease in sleep spindle density in absence seizure patients and animal models. However, whether the decrease in sleep spindle density precedes, coincides with, or follows, the SWD development remains unknown. To clarify this, we exploited Pvalb-tetracycline transactivator (tTA)::tetO-ArchT (PV-ArchT) double-transgenic mouse, which can induce an absence seizure phenotype in a time-controllable manner by expressing ArchT in PV neurons of the TRN. In these mice, EEG recordings demonstrated that a decrease in sleep spindle density occurred 1 week before the onset of typical SWDs, with the expression of ArchT. To confirm such temporal relationship observed in these genetic model mice, we used a gamma-butyrolactone (GBL) pharmacological model of SWDs. Prior to GBL administration, we administered caffeine to wild-type mice for 3 consecutive days to induce a decrease in sleep spindle density. We then administered low-dose GBL, which cannot induce SWDs in normally conditioned mice but led to the occurrence of SWDs in caffeine-conditioned mice. These findings indicate a temporal relationship in which the decrease in sleep spindle density consistently precedes SWD development. Furthermore, the decrease in sleep spindle activity may have a role in facilitating the development of SWDs. Our findings suggest that sleep spindle reductions could serve as early indicators of seizure susceptibility.
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Affiliation(s)
- Manal S Abdelaal
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
| | - Tomonobu Kato
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
- Department of System Design Engineering, Faculty of Science and Technology, Keio University, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan
| | - Akiyo Natsubori
- Sleep Disorders Project, Tokyo Metropolitan Institute of Medical Science, Setagaya-Ku, Tokyo 156-8506, Japan
| | - Kenji F Tanaka
- Division of Brain Sciences, Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan
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10
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Davoodi Nik B, Hashemi Karoii D, Favaedi R, Ramazanali F, Jahangiri M, Movaghar B, Shahhoseini M. Differential expression of ion channel coding genes in the endometrium of women experiencing recurrent implantation failures. Sci Rep 2024; 14:19822. [PMID: 39192025 PMCID: PMC11349755 DOI: 10.1038/s41598-024-70778-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024] Open
Abstract
Our study probed the differences in ion channel gene expression in the endometrium of women with Recurrent Implantation Failure (RIF) compared to fertile women. We analyzed the relative expression of genes coding for T-type Ca2+, ENaC, CFTR, and KCNQ1 channels in endometrial samples from 20 RIF-affected and 10 control women, aged 22-35, via microarray analysis and quantitative real-time PCR. Additionally, we examined DNA methylation in the regulatory region of KCNQ1 using ChIP real-time PCR. The bioinformatics component of our research included Gene Ontology analysis, protein-protein interaction networks, and signaling pathway mapping to identify key biological processes and pathways implicated in RIF. This led to the discovery of significant alterations in the expression of ion channel genes in RIF women's endometrium, most notably an overexpression of CFTR and reduced expression of SCNN1A, SCNN1B, SCNN1G, CACNA1H, and KCNQ1. A higher DNA methylation level of KCNQ1's regulatory region was also observed in RIF patients. Gene-set enrichment analysis highlighted a significant presence of genes involved with ion transport and membrane potential regulation, particularly in sodium and calcium channel complexes, which are vital for cation movement across cell membranes. Genes were also enriched in broader ion channel and transmembrane transporter complexes, underscoring their potential extensive role in cellular ion homeostasis and signaling. These findings suggest a potential involvement of ion channels in the pathology of implantation failure, offering new insights into the mechanisms behind RIF and possible therapeutic targets.
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Affiliation(s)
- Bahar Davoodi Nik
- Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran
| | - Danial Hashemi Karoii
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Raha Favaedi
- Department of Genetics, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, No. 12, Hafez St., Banihashem Sq, Resalat Ave., P.O. Box: 19395-4644, Tehran, Iran
| | - Fariba Ramazanali
- Department of Endocrinology and Female Infertility, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Maryam Jahangiri
- Department of Embryology, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, No. 12, Hafez St., Banihashem Sq, Resalat Ave., P.O. Box: 19395-4644, Tehran, Iran
| | - Bahar Movaghar
- Department of Embryology, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, No. 12, Hafez St., Banihashem Sq, Resalat Ave., P.O. Box: 19395-4644, Tehran, Iran.
| | - Maryam Shahhoseini
- Department of Genetics, Faculty of Basic Sciences and Advanced Technologies in Biology, University of Science and Culture, Tehran, Iran.
- Department of Cell and Molecular Biology, School of Biology, College of Science, University of Tehran, Tehran, Iran.
- Department of Genetics, Reproductive Biomedicine Research Centre, Royan Institute for Reproductive Biomedicine, ACECR, No. 12, Hafez St., Banihashem Sq, Resalat Ave., P.O. Box: 19395-4644, Tehran, Iran.
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11
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Jeong S, Lee BY, Rhee JS, Lee JH. G protein β subunits regulate Ca v3.3 T-type channel activity and current kinetics via interaction with the Ca v3.3 C-terminus. BIOCHIMICA ET BIOPHYSICA ACTA. BIOMEMBRANES 2024; 1866:184337. [PMID: 38763272 DOI: 10.1016/j.bbamem.2024.184337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 05/06/2024] [Accepted: 05/13/2024] [Indexed: 05/21/2024]
Abstract
Ca2+ influx through Cav3.3 T-type channel plays crucial roles in neuronal excitability and is subject to regulation by various signaling molecules. However, our understanding of the partners of Cav3.3 and the related regulatory pathways remains largely limited. To address this quest, we employed the rat Cav3.3 C-terminus as bait in yeast-two-hybrid screenings of a cDNA library, identifying rat Gβ2 as an interaction partner. Subsequent assays revealed that the interaction of Gβ2 subunit was specific to the Cav3.3 C-terminus. Through systematic dissection of the C-terminus, we pinpointed a 22 amino acid sequence (amino acids 1789-1810) as the Gβ2 interaction site. Coexpression studies of rat Cav3.3 with various Gβγ compositions were conducted in HEK-293 cells. Patch clamp recordings revealed that coexpression of Gβ2γ2 reduced Cav3.3 current density and accelerated inactivation kinetics. Interestingly, the effects were not unique to Gβ2γ2, but were mimicked by Gβ2 alone as well as other Gβγ dimers, with similar potencies. Deletion of the Gβ2 interaction site abolished the effects of Gβ2γ2. Importantly, these Gβ2 effects were reproduced in human Cav3.3. Overall, our findings provide evidence that Gβ(γ) complexes inhibit Cav3.3 channel activity and accelerate the inactivation kinetics through the Gβ interaction with the Cav3.3 C-terminus.
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Affiliation(s)
- Sua Jeong
- Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Bo-Young Lee
- Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea
| | - Jeong Seop Rhee
- Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences, Synaptic Physiology Group, Hermann-Rein-Str. 3, 37075 Göttingen, Germany
| | - Jung-Ha Lee
- Department of Life Science, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul 04107, Republic of Korea.
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12
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Lyuboslavsky P, Ordemann GJ, Kizimenko A, Brumback AC. Two contrasting mediodorsal thalamic circuits target the mouse medial prefrontal cortex. J Neurophysiol 2024; 131:876-890. [PMID: 38568510 PMCID: PMC11383385 DOI: 10.1152/jn.00456.2023] [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: 12/11/2023] [Revised: 02/28/2024] [Accepted: 03/17/2024] [Indexed: 05/09/2024] Open
Abstract
At the heart of the prefrontal network is the mediodorsal (MD) thalamus. Despite the importance of MD in a broad range of behaviors and neuropsychiatric disorders, little is known about the physiology of neurons in MD. We injected the retrograde tracer cholera toxin subunit B (CTB) into the medial prefrontal cortex (mPFC) of adult wild-type mice. We prepared acute brain slices and used current clamp electrophysiology to measure and compare the intrinsic properties of the neurons in MD that project to mPFC (MD→mPFC neurons). We show that MD→mPFC neurons are located predominantly in the medial (MD-M) and lateral (MD-L) subnuclei of MD. MD-L→mPFC neurons had shorter membrane time constants and lower membrane resistance than MD-M→mPFC neurons. Relatively increased hyperpolarization-activated cyclic nucleotide-gated (HCN) channel activity in MD-L neurons accounted for the difference in membrane resistance. MD-L neurons had a higher rheobase that resulted in less readily generated action potentials compared with MD-M→mPFC neurons. In both cell types, HCN channels supported generation of burst spiking. Increased HCN channel activity in MD-L neurons results in larger after-hyperpolarization potentials compared with MD-M neurons. These data demonstrate that the two populations of MD→mPFC neurons have divergent physiologies and support a differential role in thalamocortical information processing and potentially behavior.NEW & NOTEWORTHY To realize the potential of circuit-based therapies for psychiatric disorders that localize to the prefrontal network, we need to understand the properties of the populations of neurons that make up this network. The mediodorsal (MD) thalamus has garnered attention for its roles in executive functioning and social/emotional behaviors mediated, at least in part, by its projections to the medial prefrontal cortex (mPFC). Here, we identify and compare the physiology of the projection neurons in the two MD subnuclei that provide ascending inputs to mPFC in mice. Differences in intrinsic excitability between the two populations of neurons suggest that neuromodulation strategies targeting the prefrontal thalamocortical network will have differential effects on these two streams of thalamic input to mPFC.
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Affiliation(s)
- Polina Lyuboslavsky
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Gregory J Ordemann
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Alena Kizimenko
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
| | - Audrey C Brumback
- Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Department of Pediatrics, Dell Medical School, The University of Texas at Austin, Austin, Texas, United States
- Center for Learning and Memory, The University of Texas at Austin, Austin, Texas, United States
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13
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Sutherland HG, Jenkins B, Griffiths LR. Genetics of migraine: complexity, implications, and potential clinical applications. Lancet Neurol 2024; 23:429-446. [PMID: 38508838 DOI: 10.1016/s1474-4422(24)00026-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 01/09/2024] [Accepted: 01/11/2024] [Indexed: 03/22/2024]
Abstract
Migraine is a common neurological disorder with large burden in terms of disability for individuals and costs for society. Accurate diagnosis and effective treatments remain priorities. Understanding the genetic factors that contribute to migraine risk and symptom manifestation could improve individual management. Migraine has a strong genetic basis that includes both monogenic and polygenic forms. Some distinct, rare, familial migraine subtypes are caused by pathogenic variants in genes involved in ion transport and neurotransmitter release, suggesting an underlying vulnerability of the excitatory-inhibitory balance in the brain, which might be exacerbated by disruption of homoeostasis and lead to migraine. For more prevalent migraine subtypes, genetic studies have identified many susceptibility loci, implicating genes involved in both neuronal and vascular pathways. Genetic factors can also reveal the nature of relationships between migraine and its associated biomarkers and comorbidities and could potentially be used to identify new therapeutic targets and predict treatment response.
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Affiliation(s)
- Heidi G Sutherland
- Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Bronwyn Jenkins
- Department of Neurology, Royal North Shore Hospital, Sydney, NSW, Australia
| | - Lyn R Griffiths
- Centre for Genomics and Personalised Health, Genomics Research Centre, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia.
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14
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Zhou E, Li Q, Xu R, Pan F, Tao Y, Li X, Xue X, Wu L. Covalent conjugation with quercetin mitigates allergenicity of the bee pollen allergen Bra c p in a murine model. Food Chem 2024; 436:137722. [PMID: 37857207 DOI: 10.1016/j.foodchem.2023.137722] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 09/26/2023] [Accepted: 10/08/2023] [Indexed: 10/21/2023]
Abstract
Profilin family members are highly conserved food allergens that can cause widespread cross-allergic reactions. Our previous research has demonstrated that the covalent conjunction with quercetin can disrupt the conformational epitopes of a profilin allergen, Bra c p. In this study, we further investigated the intrinsic molecular mechanisms using molecular dynamics simulations. Moreover, the allergenic potential of Bra c p and its conjugate with quercetin was assessed in BALB/c mice. The results showed that continuous interaction with quercetin increased the molecular motion of Bra c p, causing changes to its α-helices and exposing hydrophobic residues which altered antigenic epitopes. Additionally, mice treated with Bra c p-quercetin conjugate showed reduced allergic reactions compared to those treated with Bra c p alone by regulating purine metabolism, calcium signaling, and CD4+CD25+ Tregs proportion. Quercetin conjugation decreases the allergenicity of Bra c p, providing a scientific foundation for reducing the profilin allergens in food.
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Affiliation(s)
- Enning Zhou
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Qiangqiang Li
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Rui Xu
- Institute of Food Science and Technology, Chinese Academy of Agricultural Science (CAAS), Beijing 100193, China
| | - Fei Pan
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Yuxiao Tao
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Xiangxin Li
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Xiaofeng Xue
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China
| | - Liming Wu
- State Key Laboratory of Resource Insects, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences (CAAS), Beijing 100093, China.
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15
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Lory P. The good company of T-type calcium channels : Commentary on: "T-type calcium channelosome," a review by N. Weiss and G. W. Zamponi. Pflugers Arch 2024; 476:149-150. [PMID: 38191755 DOI: 10.1007/s00424-023-02903-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/10/2024]
Affiliation(s)
- Philippe Lory
- IGF, Univ Montpellier, CNRS, INSERM, Montpellier, France.
- LabEx 'Ion Channel Science and Therapeutics', Montpellier, France.
- Institut de Génomique Fonctionnelle - CNRS, 141 rue de la Cardonille, 34094, Montpellier, France.
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Weiss N, Zamponi GW. The T-type calcium channelosome. Pflugers Arch 2024; 476:163-177. [PMID: 38036777 DOI: 10.1007/s00424-023-02891-z] [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: 10/27/2023] [Revised: 11/21/2023] [Accepted: 11/23/2023] [Indexed: 12/02/2023]
Abstract
T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.
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Affiliation(s)
- Norbert Weiss
- Department of Pathophysiology, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
| | - Gerald W Zamponi
- Department of Clinical Neurosciences, Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Canada
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Cipriani V, Vestito L, Magavern EF, Jacobsen JO, Arno G, Behr ER, Benson KA, Bertoli M, Bockenhauer D, Bowl MR, Burley K, Chan LF, Chinnery P, Conlon P, Costa M, Davidson AE, Dawson SJ, Elhassan E, Flanagan SE, Futema M, Gale DP, García-Ruiz S, Corcia CG, Griffin HR, Hambleton S, Hicks AR, Houlden H, Houlston RS, Howles SA, Kleta R, Lekkerkerker I, Lin S, Liskova P, Mitchison H, Morsy H, Mumford AD, Newman WG, Neatu R, O'Toole EA, Ong AC, Pagnamenta AT, Rahman S, Rajan N, Robinson PN, Ryten M, Sadeghi-Alavijeh O, Sayer JA, Shovlin CL, Taylor JC, Teltsh O, Tomlinson I, Tucci A, Turnbull C, van Eerde AM, Ware JS, Watts LM, Webster AR, Westbury SK, Zheng SL, Caulfield M, Smedley D. Rare disease gene association discovery from burden analysis of the 100,000 Genomes Project data. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.12.20.23300294. [PMID: 38196618 PMCID: PMC10775325 DOI: 10.1101/2023.12.20.23300294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2024]
Abstract
To discover rare disease-gene associations, we developed a gene burden analytical framework and applied it to rare, protein-coding variants from whole genome sequencing of 35,008 cases with rare diseases and their family members recruited to the 100,000 Genomes Project (100KGP). Following in silico triaging of the results, 88 novel associations were identified including 38 with existing experimental evidence. We have published the confirmation of one of these associations, hereditary ataxia with UCHL1 , and independent confirmatory evidence has recently been published for four more. We highlight a further seven compelling associations: hypertrophic cardiomyopathy with DYSF and SLC4A3 where both genes show high/specific heart expression and existing associations to skeletal dystrophies or short QT syndrome respectively; monogenic diabetes with UNC13A with a known role in the regulation of β cells and a mouse model with impaired glucose tolerance; epilepsy with KCNQ1 where a mouse model shows seizures and the existing long QT syndrome association may be linked; early onset Parkinson's disease with RYR1 with existing links to tremor pathophysiology and a mouse model with neurological phenotypes; anterior segment ocular abnormalities associated with POMK showing expression in corneal cells and with a zebrafish model with developmental ocular abnormalities; and cystic kidney disease with COL4A3 showing high renal expression and prior evidence for a digenic or modifying role in renal disease. Confirmation of all 88 associations would lead to potential diagnoses in 456 molecularly undiagnosed cases within the 100KGP, as well as other rare disease patients worldwide, highlighting the clinical impact of a large-scale statistical approach to rare disease gene discovery.
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Zhang BW, Dong H, Wu Z, Jiang X, Zou W. An Overview of the Mechanisms Involved in Neuralgia. J Inflamm Res 2023; 16:4087-4101. [PMID: 37745793 PMCID: PMC10516189 DOI: 10.2147/jir.s425966] [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: 06/14/2023] [Accepted: 08/26/2023] [Indexed: 09/26/2023] Open
Abstract
Neuralgia is a frequently occurring condition that causes chronic pain and burdens both patients and their families. Earlier research indicated that anti-inflammatory treatment, which was primarily utilized to address conditions like neuralgia, resulted in positive outcomes. However, recent years have witnessed the emergence of various novel mechanisms associated with pain-related disorders. This review provides a concise overview of the inflammatory mechanisms involved in neuralgia. It also examines recent advancements in research, exploring the influence of ion channels and synaptic proteins on neuralgia and its complications. Additionally, the interactions between these mechanisms are discussed with the aim of suggesting innovative therapeutic approaches and research directions for the management of neuralgia.
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Affiliation(s)
- Bai-Wen Zhang
- Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Hao Dong
- Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Zhe Wu
- Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
| | - Xi Jiang
- Jinzhou Medical University, Jinzhou, 121001, People’s Republic of China
| | - Wei Zou
- The Third Department of Acupuncture and Moxibustion, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, 150040, People’s Republic of China
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Koch NA, Sonnenberg L, Hedrich UBS, Lauxmann S, Benda J. Loss or gain of function? Effects of ion channel mutations on neuronal firing depend on the neuron type. Front Neurol 2023; 14:1194811. [PMID: 37292138 PMCID: PMC10244640 DOI: 10.3389/fneur.2023.1194811] [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: 03/27/2023] [Accepted: 05/03/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction Clinically relevant mutations to voltage-gated ion channels, called channelopathies, alter ion channel function, properties of ionic currents, and neuronal firing. The effects of ion channel mutations are routinely assessed and characterized as loss of function (LOF) or gain of function (GOF) at the level of ionic currents. However, emerging personalized medicine approaches based on LOF/GOF characterization have limited therapeutic success. Potential reasons are among others that the translation from this binary characterization to neuronal firing is currently not well-understood-especially when considering different neuronal cell types. In this study, we investigate the impact of neuronal cell type on the firing outcome of ion channel mutations. Methods To this end, we simulated a diverse collection of single-compartment, conductance-based neuron models that differed in their composition of ionic currents. We systematically analyzed the effects of changes in ion current properties on firing in different neuronal types. Additionally, we simulated the effects of known mutations in KCNA1 gene encoding the KV1.1 potassium channel subtype associated with episodic ataxia type 1 (EA1). Results These simulations revealed that the outcome of a given change in ion channel properties on neuronal excitability depends on neuron type, i.e., the properties and expression levels of the unaffected ionic currents. Discussion Consequently, neuron-type specific effects are vital to a full understanding of the effects of channelopathies on neuronal excitability and are an important step toward improving the efficacy and precision of personalized medicine approaches.
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Affiliation(s)
- Nils A. Koch
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, University of Tübingen, Tübingen, Germany
- Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany
| | - Lukas Sonnenberg
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, University of Tübingen, Tübingen, Germany
- Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany
| | - Ulrike B. S. Hedrich
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Stephan Lauxmann
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, University of Tübingen, Tübingen, Germany
- Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
| | - Jan Benda
- Institute of Neurobiology, Faculty of Mathematics and Natural Sciences, University of Tübingen, Tübingen, Germany
- Bernstein Center for Computational Neuroscience Tübingen, Tübingen, Germany
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20
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Török F, Tezcan K, Filippini L, Fernández-Quintero ML, Zanetti L, Liedl KR, Drexel RS, Striessnig J, Ortner NJ. Germline de novo variant F747S extends the phenotypic spectrum of CACNA1D Ca2+ channelopathies. Hum Mol Genet 2023; 32:847-859. [PMID: 36208199 PMCID: PMC9941835 DOI: 10.1093/hmg/ddac248] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 09/22/2022] [Accepted: 09/30/2022] [Indexed: 11/14/2022] Open
Abstract
Germline gain-of-function missense variants in the pore-forming Cav1.3 α1-subunit (CACNA1D gene) confer high risk for a severe neurodevelopmental disorder with or without endocrine symptoms. Here, we report a 4-week-old new-born with the novel de novo missense variant F747S with a so far not described prominent jittering phenotype in addition to symptoms previously reported for CACNA1D mutations including developmental delay, elevated aldosterone level and transient hypoglycemia. We confirmed the pathogenicity of this variant in whole-cell patch-clamp experiments with wild-type and F747S mutant channels heterologously expressed together with α2δ1 and cytosolic β3 or membrane-bound β2a subunits. Mutation F747S caused the quantitatively largest shift in the voltage dependence of activation (-28 mV) reported so far for CACNA1D germline mutations. It also shifted inactivation to more negative voltages, slowed the time course of current inactivation and slowed current deactivation upon repolarization with both co-expressed β-subunits. In silico modelling and molecular docking, simulations revealed that this gain-of-function phenotype can be explained by formation of a novel inter-domain hydrogen bond between mutant residues S747 (IIS6) with N1145 (IIIS6) stabilizing selectively the activated open channel state. F747S displayed 2-6-fold increased sensitivity for the L-type Ca2+ channel blocker isradipine compared to wild type. Our data confirm the pathogenicity of the F747S variant with very strong gain-of-function gating changes, which may contribute to the novel jittering phenotype. Increased sensitivity for isradipine suggests this drug for potential symptomatic off-label treatment for carriers of this mutation.
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Affiliation(s)
- Ferenc Török
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Kamer Tezcan
- Department of Genetics, Kaiser Permanente, Sacramento, CA 95825, USA
| | - Ludovica Filippini
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Monica L Fernández-Quintero
- Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Lucia Zanetti
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Klaus R Liedl
- Department of General, Inorganic and Theoretical Chemistry, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Raphaela S Drexel
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Jörg Striessnig
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
| | - Nadine J Ortner
- Department of Pharmacology and Toxicology, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck 6020, Austria
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21
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Matthews LG, Puryear CB, Correia SS, Srinivasan S, Belfort GM, Pan MK, Kuo SH. T-type calcium channels as therapeutic targets in essential tremor and Parkinson's disease. Ann Clin Transl Neurol 2023; 10:462-483. [PMID: 36738196 PMCID: PMC10109288 DOI: 10.1002/acn3.51735] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 02/05/2023] Open
Abstract
Neuronal action potential firing patterns are key components of healthy brain function. Importantly, restoring dysregulated neuronal firing patterns has the potential to be a promising strategy in the development of novel therapeutics for disorders of the central nervous system. Here, we review the pathophysiology of essential tremor and Parkinson's disease, the two most common movement disorders, with a focus on mechanisms underlying the genesis of abnormal firing patterns in the implicated neural circuits. Aberrant burst firing of neurons in the cerebello-thalamo-cortical and basal ganglia-thalamo-cortical circuits contribute to the clinical symptoms of essential tremor and Parkinson's disease, respectively, and T-type calcium channels play a key role in regulating this activity in both the disorders. Accordingly, modulating T-type calcium channel activity has received attention as a potentially promising therapeutic approach to normalize abnormal burst firing in these diseases. In this review, we explore the evidence supporting the theory that T-type calcium channel blockers can ameliorate the pathophysiologic mechanisms underlying essential tremor and Parkinson's disease, furthering the case for clinical investigation of these compounds. We conclude with key considerations for future investigational efforts, providing a critical framework for the development of much needed agents capable of targeting the dysfunctional circuitry underlying movement disorders such as essential tremor, Parkinson's disease, and beyond.
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Affiliation(s)
| | - Corey B Puryear
- Praxis Precision Medicines, Boston, Massachusetts, 02110, USA
| | | | - Sharan Srinivasan
- Praxis Precision Medicines, Boston, Massachusetts, 02110, USA.,Department of Neurology, University of Michigan, Ann Arbor, Michigan, 48109, USA
| | | | - Ming-Kai Pan
- Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei, 10051, Taiwan.,Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, 10617, Taiwan.,Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan.,Cerebellar Research Center, National Taiwan University Hospital, Yun-Lin Branch, Yun-Lin, 64041, Taiwan
| | - Sheng-Han Kuo
- Department of Neurology, Columbia University, New York, New York, 10032, USA.,Initiative for Columbia Ataxia and Tremor, Columbia University, New York, New York, 10032, USA
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22
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Jeong S, Shim JS, Sin SK, Park KS, Lee JH. Phosphorylation states greatly regulate the activity and gating properties of Ca v 3.1 T-type Ca 2+ channels. J Cell Physiol 2023; 238:210-226. [PMID: 36502489 DOI: 10.1002/jcp.30920] [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: 08/18/2022] [Revised: 10/21/2022] [Accepted: 11/10/2022] [Indexed: 12/14/2022]
Abstract
Cav 3.1 T-type Ca2+ channels play pivotal roles in neuronal low-threshold spikes, visceral pain, and pacemaker activity. Phosphorylation has been reported to potently regulate the activity and gating properties of Cav 3.1 channels. However, systematic identification of phosphorylation sites (phosphosites) in Cav 3.1 channel has been poorly investigated. In this work, we analyzed rat Cav 3.1 protein expressed in HEK-293 cells by mass spectrometry, identified 30 phosphosites located at the cytoplasmic regions, and illustrated them as a Cav 3.1 phosphorylation map which includes the reported mouse Cav 3.1 phosphosites. Site-directed mutagenesis of the phosphosites to Ala residues and functional analysis of the phospho-silent Cav 3.1 mutants expressed in Xenopus oocytes showed that the phospho-silent mutation of the N-terminal Ser18 reduced its current amplitude with accelerated current kinetics and negatively shifted channel availability. Remarkably, the phospho-silent mutations of the C-terminal Ser residues (Ser1924, Ser2001, Ser2163, Ser2166, or Ser2189) greatly reduced their current amplitude without altering the voltage-dependent gating properties. In contrast, the phosphomimetic Asp mutations of Cav 3.1 on the N- and C-terminal Ser residues reversed the effects of the phospho-silent mutations. Collectively, these findings demonstrate that the multiple phosphosites of Cav 3.1 at the N- and C-terminal regions play crucial roles in the regulation of the channel activity and voltage-dependent gating properties.
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Affiliation(s)
- Sua Jeong
- Department of Life Science, Sogang University, Seoul, South Korea
| | - Ji Seon Shim
- Department of Physiology, Kyung-Hee University, Seoul, South Korea
| | - Seok Kyo Sin
- Department of Physiology, Kyung-Hee University, Seoul, South Korea
| | - Kang-Sik Park
- Department of Physiology, Kyung-Hee University, Seoul, South Korea
| | - Jung-Ha Lee
- Department of Life Science, Sogang University, Seoul, South Korea
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23
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Abstract
The CACNA1C gene encodes the pore-forming subunit of the CaV1.2 L-type Ca2+ channel, a critical component of membrane physiology in multiple tissues, including the heart, brain, and immune system. As such, mutations altering the function of these channels have the potential to impact a wide array of cellular functions. The first mutations identified within CACNA1C were shown to cause a severe, multisystem disorder known as Timothy syndrome (TS), which is characterized by neurodevelopmental deficits, long-QT syndrome, life-threatening cardiac arrhythmias, craniofacial abnormalities, and immune deficits. Since this initial description, the number and variety of disease-associated mutations identified in CACNA1C have grown tremendously, expanding the range of phenotypes observed in affected patients. CACNA1C channelopathies are now known to encompass multisystem phenotypes as described in TS, as well as more selective phenotypes where patients may exhibit predominantly cardiac or neurological symptoms. Here, we review the impact of genetic mutations on CaV1.2 function and the resultant physiological consequences.
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Affiliation(s)
- Kevin G Herold
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John W Hussey
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Ivy E Dick
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA.
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24
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El Ghaleb Y, Flucher BE. Ca V3.3 Channelopathies. Handb Exp Pharmacol 2023; 279:263-288. [PMID: 36592228 DOI: 10.1007/164_2022_631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
CaV3.3 is the third member of the low-voltage-activated calcium channel family and the last to be recognized as disease gene. Previously, CACNA1I, the gene encoding CaV3.3, had been described as schizophrenia risk gene. More recently, de novo missense mutations in CACNA1I were identified in patients with variable degrees of neurodevelopmental disease with and without epilepsy. Their functional characterization indicated gain-of-function effects resulting in increased calcium load and hyperexcitability of neurons expressing CaV3.3. The amino acids mutated in the CaV3.3 disease variants are located in the vicinity of the channel's activation gate and thus are classified as gate-modifying channelopathy mutations. A persistent calcium leak during rest and prolonged calcium spikes due to increased voltage sensitivity of activation and slowed kinetics of channel inactivation, respectively, may be causal for the neurodevelopmental defects. The prominent expression of CaV3.3 in thalamic reticular nucleus neurons and its essential role in generating the rhythmic thalamocortical network activity are consistent with a role of the mutated channels in the etiology of epileptic seizures and thus suggest T-type channel blockers as a viable treatment option.
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Affiliation(s)
- Yousra El Ghaleb
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria
| | - Bernhard E Flucher
- Institute of Physiology, Medical University Innsbruck, Innsbruck, Austria.
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25
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Bamgboye MA, Traficante MK, Owoyemi J, DiSilvestre D, Vieira DCO, Dick IE. Impaired Ca V1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8. J Mol Cell Cardiol 2022; 173:92-100. [PMID: 36272554 PMCID: PMC10583761 DOI: 10.1016/j.yjmcc.2022.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 10/12/2022] [Accepted: 10/16/2022] [Indexed: 11/23/2022]
Abstract
Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in CaV1.2 have been identified, increasing the need for targeted therapies. As many of these mutations reduce channel inactivation; resulting in excess Ca2+ entry during the action potential, calcium channel blockers (CCBs) would seem to represent a promising treatment option. Yet CCBs have been unsuccessful in the treatment of LQT8. Here, we demonstrate that this lack of efficacy likely stems from the impact of the mutations on CaV1.2 channel inactivation. As CCBs are known to preferentially bind to the inactivated state of the channel, mutation-dependent deficits in inactivation result in a decrease in use-dependent block of the mutant channel. Further, application of the CCB verapamil to induced pluripotent stem cell (iPSC) derived cardiomyocytes from an LQT8 patient demonstrates that this loss of use-dependent block translates to a lack of efficacy in correcting the LQT phenotype. As a growing number of channelopathic mutations demonstrate effects on channel inactivation, reliance on state-dependent blockers may leave a growing population of patients without a viable treatment option. This biophysical understanding of the interplay between inactivation deficits and state-dependent block may provide a new avenue to guide the development of improved therapies.
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Affiliation(s)
- Moradeke A Bamgboye
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America
| | - Maria K Traficante
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America
| | - Josiah Owoyemi
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America
| | - Deborah DiSilvestre
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America
| | - Daiana C O Vieira
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America
| | - Ivy E Dick
- Department of Physiology, University of Maryland, School of Medicine, Baltimore, MD, United States of America.
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26
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Shin SM, Lauzadis J, Itson-Zoske B, Cai Y, Fan F, Natarajan GK, Kwok WM, Puopolo M, Hogan QH, Yu H. Targeting intrinsically disordered regions facilitates discovery of calcium channels 3.2 inhibitory peptides for adeno-associated virus-mediated peripheral analgesia. Pain 2022; 163:2466-2484. [PMID: 35420557 PMCID: PMC9562599 DOI: 10.1097/j.pain.0000000000002650] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 03/19/2022] [Accepted: 03/23/2022] [Indexed: 11/27/2022]
Abstract
ABSTRACT Ample data support a prominent role of peripheral T-type calcium channels 3.2 (Ca V 3.2) in generating pain states. Development of primary sensory neuron-specific inhibitors of Ca V 3.2 channels is an opportunity for achieving effective analgesic therapeutics, but success has been elusive. Small peptides, especially those derived from natural proteins as inhibitory peptide aptamers (iPAs), can produce highly effective and selective blockade of specific nociceptive molecular pathways to reduce pain with minimal off-target effects. In this study, we report the engineering of the potent and selective iPAs of Ca V 3.2 from the intrinsically disordered regions (IDRs) of Ca V 3.2 intracellular segments. Using established prediction algorithms, we localized the IDRs in Ca V 3.2 protein and identified several Ca V 3.2iPA candidates that significantly reduced Ca V 3.2 current in HEK293 cells stably expressing human wide-type Ca V 3.2. Two prototype Ca V 3.2iPAs (iPA1 and iPA2) derived from the IDRs of Ca V 3.2 intracellular loops 2 and 3, respectively, were expressed selectively in the primary sensory neurons of dorsal root ganglia in vivo using recombinant adeno-associated virus (AAV), which produced sustained inhibition of calcium current conducted by Ca V 3.2/T-type channels and significantly attenuated both evoked and spontaneous pain behavior in rats with neuropathic pain after tibial nerve injury. Recordings from dissociated sensory neurons showed that AAV-mediated Ca V 3.2iPA expression suppressed neuronal excitability, suggesting that Ca V 3.2iPA treatment attenuated pain by reversal of injury-induced neuronal hypersensitivity. Collectively, our results indicate that Ca V 3.2iPAs are promising analgesic leads that, combined with AAV-mediated delivery in anatomically targeted sensory ganglia, have the potential to be a selective peripheral Ca V 3.2-targeting strategy for clinical treatment of pain.
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Affiliation(s)
- Seung Min Shin
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Justas Lauzadis
- Department of Anesthesiology, Stony Brook University, Stony Brook, NY, United States
| | - Brandon Itson-Zoske
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Yongsong Cai
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
- Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Fan Fan
- Department of Pharmacology and Toxicology, The University of Mississippi Medical Center, Jackson, MS, United States
| | - Gayathri K. Natarajan
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Wai-Meng Kwok
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Michelino Puopolo
- Department of Anesthesiology, Stony Brook University, Stony Brook, NY, United States
| | - Quinn H. Hogan
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Hongwei Yu
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, United States
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27
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Subbamanda YD, Bhargava A. Intercommunication between Voltage-Gated Calcium Channels and Estrogen Receptor/Estrogen Signaling: Insights into Physiological and Pathological Conditions. Cells 2022; 11:cells11233850. [PMID: 36497108 PMCID: PMC9739980 DOI: 10.3390/cells11233850] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 11/25/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
Voltage-gated calcium channels (VGCCs) and estrogen receptors are important cellular proteins that have been shown to interact with each other across varied cells and tissues. Estrogen hormone, the ligand for estrogen receptors, can also exert its effects independent of estrogen receptors that collectively constitute non-genomic mechanisms. Here, we provide insights into the VGCC regulation by estrogen and the possible mechanisms involved therein across several cell types. Notably, most of the interaction is described in neuronal and cardiovascular tissues given the importance of VGCCs in these electrically excitable tissues. We describe the modulation of various VGCCs by estrogen known so far in physiological conditions and pathological conditions. We observed that in most in vitro studies higher concentrations of estrogen were used while a handful of in vivo studies used meager concentrations resulting in inhibition or upregulation of VGCCs, respectively. There is a need for more relevant physiological assays to study the regulation of VGCCs by estrogen. Additionally, other interacting receptors and partners need to be identified that may be involved in exerting estrogen receptor-independent effects of estrogen.
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28
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Bamgboye MA, Herold KG, Vieira DC, Traficante MK, Rogers PJ, Ben-Johny M, Dick IE. CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms. J Gen Physiol 2022; 154:e202213209. [PMID: 36167061 PMCID: PMC9524202 DOI: 10.1085/jgp.202213209] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 08/09/2022] [Accepted: 09/13/2022] [Indexed: 01/17/2023] Open
Abstract
The first pathogenic mutation in CaV1.2 was identified in 2004 and was shown to cause a severe multisystem disorder known as Timothy syndrome (TS). The mutation was localized to the distal S6 region of the channel, a region known to play a major role in channel activation. TS patients suffer from life-threatening cardiac symptoms as well as significant neurodevelopmental deficits, including autism spectrum disorder (ASD). Since this discovery, the number and variety of mutations identified in CaV1.2 have grown tremendously, and the distal S6 regions remain a frequent locus for many of these mutations. While the majority of patients harboring these mutations exhibit cardiac symptoms that can be well explained by known pathogenic mechanisms, the same cannot be said for the ASD or neurodevelopmental phenotypes seen in some patients, indicating a gap in our understanding of the pathogenesis of CaV1.2 channelopathies. Here, we use whole-cell patch clamp, quantitative Ca2+ imaging, and single channel recordings to expand the known mechanisms underlying the pathogenesis of CaV1.2 channelopathies. Specifically, we find that mutations within the S6 region can exert independent and separable effects on activation, voltage-dependent inactivation (VDI), and Ca2+-dependent inactivation (CDI). Moreover, the mechanisms underlying the CDI effects of these mutations are varied and include altered channel opening and possible disruption of CDI transduction. Overall, these results provide a structure-function framework to conceptualize the role of S6 mutations in pathophysiology and offer insight into the biophysical defects associated with distinct clinical manifestations.
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Affiliation(s)
- Moradeke A. Bamgboye
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
| | - Kevin G. Herold
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
| | - Daiana C.O. Vieira
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
| | - Maria K. Traficante
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
| | - Philippa J. Rogers
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
| | - Manu Ben-Johny
- Department of Physiology and Biophysics, Columbia University, New York, NY
| | - Ivy E. Dick
- Department of Physiology, University of Maryland School of Medicine, Baltimore, MD
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29
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Eickhoff A, Tjaden J, Stahlke S, Vorgerd M, Theis V, Matschke V, Theiss C. Effects of progesterone on T-type-Ca 2+-channel expression in Purkinje cells. Neural Regen Res 2022; 17:2465-2471. [PMID: 35535898 PMCID: PMC9120685 DOI: 10.4103/1673-5374.339008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Plasticity of cerebellar Purkinje cells (PC) is influenced by progesterone via the classical progesterone receptors PR-A and PR-B by stimulating dendritogenesis, spinogenesis, and synaptogenesis in these cells. Dissociated PC cultures were used to analyze progesterone effects at a molecular level on the voltage-gated T-type-Ca2+-channels Cav3.1, Cav3.2, and Cav3.3 as they helped determine neuronal plasticity by regulating Ca2+-influx in neuronal cells. The results showed direct effects of progesterone on the mRNA expression of T-type-Ca2+-channels, as well as on the protein kinases A and C being involved in downstream signaling pathways that play an important role in neuronal plasticity. For the mRNA expression studies of T-type-Ca2+-channels and protein kinases of the signaling cascade, laser microdissection and purified PC cultures of different maturation stages were used. Immunohistochemical staining was also performed to characterize the localization of T-type-Ca2+-channels in PC. Experimental progesterone treatment was performed on the purified PC culture for 24 and 48 hours. Our results show that progesterone increases the expression of Cav3.1 and Cav3.3 and associated protein kinases A and C in PC at the mRNA level within 48 hours after treatment at latest. These effects extend the current knowledge of the function of progesterone in the central nervous system and provide an explanatory approach for its influence on neuronal plasticity.
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Affiliation(s)
- Annika Eickhoff
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
| | - Jonas Tjaden
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
| | - Sarah Stahlke
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
| | - Matthias Vorgerd
- Department of Neurology, Neuromuscular Center Ruhrgebiet, University Hospital Bergmannsheil, Ruhr-Universität Bochum, Bochum, Germany
| | - Verena Theis
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
| | - Veronika Matschke
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
| | - Carsten Theiss
- Department of Cytology, Institute of Anatomy, Ruhr-University Bochum, Bochum, Germany
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30
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T-Type Calcium Channels: A Mixed Blessing. Int J Mol Sci 2022; 23:ijms23179894. [PMID: 36077291 PMCID: PMC9456242 DOI: 10.3390/ijms23179894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022] Open
Abstract
The role of T-type calcium channels is well established in excitable cells, where they preside over action potential generation, automaticity, and firing. They also contribute to intracellular calcium signaling, cell cycle progression, and cell fate; and, in this sense, they emerge as key regulators also in non-excitable cells. In particular, their expression may be considered a prognostic factor in cancer. Almost all cancer cells express T-type calcium channels to the point that it has been considered a pharmacological target; but, as the drugs used to reduce their expression are not completely selective, several complications develop, especially within the heart. T-type calcium channels are also involved in a specific side effect of several anticancer agents, that act on microtubule transport, increase the expression of the channel, and, thus, the excitability of sensory neurons, and make the patient more sensitive to pain. This review puts into context the relevance of T-type calcium channels in cancer and in chemotherapy side effects, considering also the cardiotoxicity induced by new classes of antineoplastic molecules.
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31
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Discovery of pimozide derivatives as novel T-type calcium channel inhibitors with little binding affinity to dopamine D2 receptors for treatment of somatic and visceral pain. Eur J Med Chem 2022; 243:114716. [DOI: 10.1016/j.ejmech.2022.114716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 08/17/2022] [Accepted: 08/23/2022] [Indexed: 11/23/2022]
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32
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Oniani T, Vinnenberg L, Chaudhary R, Schreiber JA, Riske K, Williams B, Pape HC, White JA, Junker A, Seebohm G, Meuth SG, Hundehege P, Budde T, Zobeiri M. Effects of Axonal Demyelination, Inflammatory Cytokines and Divalent Cation Chelators on Thalamic HCN Channels and Oscillatory Bursting. Int J Mol Sci 2022; 23:ijms23116285. [PMID: 35682964 PMCID: PMC9181513 DOI: 10.3390/ijms23116285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 05/31/2022] [Accepted: 05/31/2022] [Indexed: 12/13/2022] Open
Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is characterized by the progressive loss of oligodendrocytes and myelin and is associated with thalamic dysfunction. Cuprizone (CPZ)-induced general demyelination in rodents is a valuable model for studying different aspects of MS pathology. CPZ feeding is associated with the altered distribution and expression of different ion channels along neuronal somata and axons. However, it is largely unknown whether the copper chelator CPZ directly influences ion channels. Therefore, we assessed the effects of different divalent cations (copper; zinc) and trace metal chelators (EDTA; Tricine; the water-soluble derivative of CPZ, BiMPi) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that are major mediators of thalamic function and pathology. In addition, alterations of HCN channels induced by CPZ treatment and MS-related proinflammatory cytokines (IL-1β; IL-6; INF-α; INF-β) were characterized in C57Bl/6J mice. Thus, the hyperpolarization-activated inward current (Ih) was recorded in thalamocortical (TC) neurons and heterologous expression systems (mHCN2 expressing HEK cells; hHCN4 expressing oocytes). A number of electrophysiological characteristics of Ih (potential of half-maximal activation (V0.5); current density; activation kinetics) were unchanged following the extracellular application of trace metals and divalent cation chelators to native neurons, cell cultures or oocytes. Mice were fed a diet containing 0.2% CPZ for 35 days, resulting in general demyelination in the brain. Withdrawal of CPZ from the diet resulted in rapid remyelination, the effects of which were assessed at three time points after stopping CPZ feeding (Day1, Day7, Day25). In TC neurons, Ih was decreased on Day1 and Day25 and revealed a transient increased availability on Day7. In addition, we challenged naive TC neurons with INF-α and IL-1β. It was found that Ih parameters were differentially altered by the application of the two cytokines to thalamic cells, while IL-1β increased the availability of HCN channels (depolarized V0.5; increased current density) and the excitability of TC neurons (depolarized resting membrane potential (RMP); increased the number of action potentials (APs); produced a larger voltage sag; promoted higher input resistance; increased the number of burst spikes; hyperpolarized the AP threshold), INF-α mediated contrary effects. The effect of cytokine modulation on thalamic bursting was further assessed in horizontal slices and a computational model of slow thalamic oscillations. Here, IL-1β and INF-α increased and reduced oscillatory bursting, respectively. We conclude that HCN channels are not directly modulated by trace metals and divalent cation chelators but are subject to modulation by different MS-related cytokines.
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Affiliation(s)
- Tengiz Oniani
- Institute of Physiology I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, D-48149 Münster, Germany; (T.O.); (R.C.); (H.-C.P.); (M.Z.)
| | - Laura Vinnenberg
- Department of Neurology with Institute of Translational Neurology, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany; (L.V.); (P.H.)
| | - Rahul Chaudhary
- Institute of Physiology I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, D-48149 Münster, Germany; (T.O.); (R.C.); (H.-C.P.); (M.Z.)
| | - Julian A. Schreiber
- Institute of Pharmaceutical and Medicinal Chemistry, Westfälische Wilhelms-Universität, Corren-Str. 48, D-48149 Münster, Germany;
- Cellular Electrophysiology and Molecular Biology, Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Robert-Koch-Str. 45, D-48149 Münster, Germany;
| | - Kathrin Riske
- European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität, Waldeyer-Str. 15, D-48149 Münster, Germany; (K.R.); (A.J.)
| | - Brandon Williams
- Center for Systems Neuroscience, Neurophotonics Center, Department of Biomedical Engineering, Boston University, 610 Commonwealth Ave., Boston, MA 02215, USA; (B.W.); (J.A.W.)
| | - Hans-Christian Pape
- Institute of Physiology I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, D-48149 Münster, Germany; (T.O.); (R.C.); (H.-C.P.); (M.Z.)
| | - John A. White
- Center for Systems Neuroscience, Neurophotonics Center, Department of Biomedical Engineering, Boston University, 610 Commonwealth Ave., Boston, MA 02215, USA; (B.W.); (J.A.W.)
| | - Anna Junker
- European Institute for Molecular Imaging (EIMI), Westfälische Wilhelms-Universität, Waldeyer-Str. 15, D-48149 Münster, Germany; (K.R.); (A.J.)
| | - Guiscard Seebohm
- Cellular Electrophysiology and Molecular Biology, Department of Cardiovascular Medicine, Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Robert-Koch-Str. 45, D-48149 Münster, Germany;
| | - Sven G. Meuth
- Neurology Clinic, University Clinic Düsseldorf, Moorenstraße 5, D-40225 Düsseldorf, Germany;
| | - Petra Hundehege
- Department of Neurology with Institute of Translational Neurology, Albert-Schweitzer-Campus 1, D-48149 Münster, Germany; (L.V.); (P.H.)
| | - Thomas Budde
- Institute of Physiology I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, D-48149 Münster, Germany; (T.O.); (R.C.); (H.-C.P.); (M.Z.)
- Correspondence:
| | - Mehrnoush Zobeiri
- Institute of Physiology I, Westfälische Wilhelms-Universität, Robert-Koch-Str. 27a, D-48149 Münster, Germany; (T.O.); (R.C.); (H.-C.P.); (M.Z.)
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The Genetic Diagnosis of Ultrarare DEEs: An Ongoing Challenge. Genes (Basel) 2022; 13:genes13030500. [PMID: 35328054 PMCID: PMC8953579 DOI: 10.3390/genes13030500] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/04/2022] [Accepted: 03/10/2022] [Indexed: 02/06/2023] Open
Abstract
Epileptic encephalopathies (EEs) and developmental and epileptic encephalopathies (DEEs) are a group of severe early-onset neurodevelopmental disorders (NDDs). In recent years, next-generation equencing (NGS) technologies enabled the discovery of numerous genes involved in these conditions. However, more than 50% of patients remained undiagnosed. A major obstacle lies in the high degree of genetic heterogeneity and the wide phenotypic variability that has characterized these disorders. Interpreting a large amount of NGS data is also a crucial challenge. This study describes a dynamic diagnostic procedure used to investigate 17 patients with DEE or EE with previous negative or inconclusive genetic testing by whole-exome sequencing (WES), leading to a definite diagnosis in about 59% of participants. Biallelic mutations caused most of the diagnosed cases (50%), and a pathogenic somatic mutation resulted in 10% of the subjects. The high diagnostic yield reached highlights the relevance of the scientific approach, the importance of the reverse phenotyping strategy, and the involvement of a dedicated multidisciplinary team. The study emphasizes the role of recessive and somatic variants, new genetic mechanisms, and the complexity of genotype–phenotype associations. In older patients, WES results could end invasive diagnostic procedures and allow a more accurate transition. Finally, an early pursued diagnosis is essential for comprehensive care of patients, precision approach, knowledge of prognosis, patient and family planning, and quality of life.
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Lanzetti S, Di Biase V. Small Molecules as Modulators of Voltage-Gated Calcium Channels in Neurological Disorders: State of the Art and Perspectives. Molecules 2022; 27:1312. [PMID: 35209100 PMCID: PMC8879281 DOI: 10.3390/molecules27041312] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/11/2022] [Accepted: 02/11/2022] [Indexed: 01/03/2023] Open
Abstract
Voltage-gated calcium channels (VGCCs) are widely expressed in the brain, heart and vessels, smooth and skeletal muscle, as well as in endocrine cells. VGCCs mediate gene transcription, synaptic and neuronal structural plasticity, muscle contraction, the release of hormones and neurotransmitters, and membrane excitability. Therefore, it is not surprising that VGCC dysfunction results in severe pathologies, such as cardiovascular conditions, neurological and psychiatric disorders, altered glycemic levels, and abnormal smooth muscle tone. The latest research findings and clinical evidence increasingly show the critical role played by VGCCs in autism spectrum disorders, Parkinson's disease, drug addiction, pain, and epilepsy. These findings outline the importance of developing selective calcium channel inhibitors and modulators to treat such prevailing conditions of the central nervous system. Several small molecules inhibiting calcium channels are currently used in clinical practice to successfully treat pain and cardiovascular conditions. However, the limited palette of molecules available and the emerging extent of VGCC pathophysiology require the development of additional drugs targeting these channels. Here, we provide an overview of the role of calcium channels in neurological disorders and discuss possible strategies to generate novel therapeutics.
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Affiliation(s)
| | - Valentina Di Biase
- Institute of Pharmacology, Department of Medical Statistics, Informatics and Health Economics, Medical University of Innsbruck, Peter-Mayr Strasse 1, A-6020 Innsbruck, Austria;
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35
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Ion Channel Partnerships: Odd and Not-So-Odd Couples Controlling Neuronal Ion Channel Function. Int J Mol Sci 2022; 23:ijms23041953. [PMID: 35216068 PMCID: PMC8878034 DOI: 10.3390/ijms23041953] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 12/04/2022] Open
Abstract
The concerted function of the large number of ion channels expressed in excitable cells, including brain neurons, shapes diverse signaling events by controlling the electrical properties of membranes. It has long been recognized that specific groups of ion channels are functionally coupled in mediating ionic fluxes that impact membrane potential, and that these changes in membrane potential impact ion channel gating. Recent studies have identified distinct sets of ion channels that can also physically and functionally associate to regulate the function of either ion channel partner beyond that afforded by changes in membrane potential alone. Here, we review canonical examples of such ion channel partnerships, in which a Ca2+ channel is partnered with a Ca2+-activated K+ channel to provide a dedicated route for efficient coupling of Ca2+ influx to K+ channel activation. We also highlight examples of non-canonical ion channel partnerships between Ca2+ channels and voltage-gated K+ channels that are not intrinsically Ca2+ sensitive, but whose partnership nonetheless yields enhanced regulation of one or the other ion channel partner. We also discuss how these ion channel partnerships can be shaped by the subcellular compartments in which they are found and provide perspectives on how recent advances in techniques to identify proteins in close proximity to one another in native cells may lead to an expanded knowledge of other ion channel partnerships.
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36
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Maksemous N, Blayney CD, Sutherland HG, Smith RA, Lea RA, Tran KN, Ibrahim O, McArthur JR, Haupt LM, Cader MZ, Finol-Urdaneta RK, Adams DJ, Griffiths LR. Investigation of CACNA1I Cav3.3 Dysfunction in Hemiplegic Migraine. Front Mol Neurosci 2022; 15:892820. [PMID: 35928792 PMCID: PMC9345121 DOI: 10.3389/fnmol.2022.892820] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/13/2022] [Indexed: 01/12/2023] Open
Abstract
Familial hemiplegic migraine (FHM) is a severe neurogenetic disorder for which three causal genes, CACNA1A, SCN1A, and ATP1A2, have been implicated. However, more than 80% of referred diagnostic cases of hemiplegic migraine (HM) are negative for exonic mutations in these known FHM genes, suggesting the involvement of other genes. Using whole-exome sequencing data from 187 mutation-negative HM cases, we identified rare variants in the CACNA1I gene encoding the T-type calcium channel Cav3.3. Burden testing of CACNA1I variants showed a statistically significant increase in allelic burden in the HM case group compared to gnomAD (OR = 2.30, P = 0.00005) and the UK Biobank (OR = 2.32, P = 0.0004) databases. Dysfunction in T-type calcium channels, including Cav3.3, has been implicated in a range of neurological conditions, suggesting a potential role in HM. Using patch-clamp electrophysiology, we compared the biophysical properties of five Cav3.3 variants (p.R111G, p.M128L, p.D302G, p.R307H, and p.Q1158H) to wild-type (WT) channels expressed in HEK293T cells. We observed numerous functional alterations across the channels with Cav3.3-Q1158H showing the greatest differences compared to WT channels, including reduced current density, right-shifted voltage dependence of activation and inactivation, and slower current kinetics. Interestingly, we also found significant differences in the conductance properties exhibited by the Cav3.3-R307H and -Q1158H variants compared to WT channels under conditions of acidosis and alkalosis. In light of these data, we suggest that rare variants in CACNA1I may contribute to HM etiology.
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Affiliation(s)
- Neven Maksemous
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Claire D Blayney
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
| | - Heidi G Sutherland
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Robert A Smith
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Rod A Lea
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Kim Ngan Tran
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Omar Ibrahim
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - Jeffrey R McArthur
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
| | - Larisa M Haupt
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
| | - M Zameel Cader
- Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom
| | - Rocio K Finol-Urdaneta
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
| | - David J Adams
- Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia
| | - Lyn R Griffiths
- Genomics Research Centre, The Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia
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Khokhar M, Tomo S, Gadwal A, Purohit P. Multi-omics integration and interactomics reveals molecular networks and regulators of the beneficial effect of yoga and exercise. Int J Yoga 2022; 15:25-39. [PMID: 35444372 PMCID: PMC9015089 DOI: 10.4103/ijoy.ijoy_146_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 10/19/2021] [Accepted: 12/09/2021] [Indexed: 11/16/2022] Open
Abstract
Background Yoga is a multifaceted spiritual tool that helps in maintaining health, peace of mind, and positive thoughts. In the context of asana, yoga is similar to physical exercise. This study aims to construct a molecular network to find hub genes that play important roles in physical exercise and yoga. Methodology We combined differentially expressed genes (DEGs) in yoga and exercise using computational bioinformatics from publicly available gene expression omnibus (GEO) datasets and identified the codifferentially expressed mRNAs with GEO2R. The co-DEGs were divided into four different groups and each group was subjected to protein-protein interaction (PPI) network, pathways analysis, and gene ontology. Results Our study identified immunological modulation as a dominant target of differential expression in yoga and exercise. Yoga predominantly modulated genes affecting the Th1 and NK cells, whereas Cytokines, Macrophage activation, and oxidative stress were affected by exercise. We also observed that while yoga regulated genes for two main physiological functions of the body, namely Circadian Rhythm (BHLHE40) and immunity (LBP, T-box transcription factor 21, CEACAM1), exercise-regulated genes involved in apoptosis (BAG3, protein kinase C alpha), angiogenesis, and cellular adhesion (EPH receptor A1). Conclusion The dissimilarity in the genetic expression patterns in Yoga and exercise highlights the discrete effect of each in biological systems. The integration and convergences of multi-omics signals can provide deeper and comprehensive insights into the various biological mechanisms through which yoga and exercise exert their beneficial effects and opens up potential newer research areas.
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Affiliation(s)
- Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Sojit Tomo
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India,Department of Biochemistry, Santosh Medical College, Ghaziabad, Uttar Pradesh, India
| | - Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India,Address for correspondence: Dr. Purvi Purohit, Department of Biochemistry, All India Institute of Medical Sciences, Basni Industrial Area, Phase-2, Jodhpur - 342 005, Rajasthan, India. E-mail:
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38
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El Ghaleb Y, Schneeberger PE, Fernández-Quintero ML, Geisler SM, Pelizzari S, Polstra AM, van Hagen JM, Denecke J, Campiglio M, Liedl KR, Stevens CA, Person RE, Rentas S, Marsh ED, Conlin LK, Tuluc P, Kutsche K, Flucher BE. CACNA1I gain-of-function mutations differentially affect channel gating and cause neurodevelopmental disorders. Brain 2021; 144:2092-2106. [PMID: 33704440 PMCID: PMC8422349 DOI: 10.1093/brain/awab101] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 01/05/2021] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
T-type calcium channels (Cav3.1 to Cav3.3) regulate low-threshold calcium spikes, burst firing and rhythmic oscillations of neurons and are involved in sensory processing, sleep, and hormone and neurotransmitter release. Here, we examined four heterozygous missense variants in CACNA1I, encoding the Cav3.3 channel, in patients with variable neurodevelopmental phenotypes. The p.(Ile860Met) variant, affecting a residue in the putative channel gate at the cytoplasmic end of the IIS6 segment, was identified in three family members with variable cognitive impairment. The de novo p.(Ile860Asn) variant, changing the same amino acid residue, was detected in a patient with severe developmental delay and seizures. In two additional individuals with global developmental delay, hypotonia, and epilepsy, the variants p.(Ile1306Thr) and p.(Met1425Ile), substituting residues at the cytoplasmic ends of IIIS5 and IIIS6, respectively, were found. Because structure modelling indicated that the amino acid substitutions differentially affect the mobility of the channel gate, we analysed possible effects on Cav3.3 channel function using patch-clamp analysis in HEK293T cells. The mutations resulted in slowed kinetics of current activation, inactivation, and deactivation, and in hyperpolarizing shifts of the voltage-dependence of activation and inactivation, with Cav3.3-I860N showing the strongest and Cav3.3-I860M the weakest effect. Structure modelling suggests that by introducing stabilizing hydrogen bonds the mutations slow the kinetics of the channel gate and cause the gain-of-function effect in Cav3.3 channels. The gating defects left-shifted and increased the window currents, resulting in increased calcium influx during repetitive action potentials and even at resting membrane potentials. Thus, calcium toxicity in neurons expressing the Cav3.3 variants is one likely cause of the neurodevelopmental phenotype. Computer modelling of thalamic reticular nuclei neurons indicated that the altered gating properties of the Cav3.3 disease variants lower the threshold and increase the duration and frequency of action potential firing. Expressing the Cav3.3-I860N/M mutants in mouse chromaffin cells shifted the mode of firing from low-threshold spikes and rebound burst firing with wild-type Cav3.3 to slow oscillations with Cav3.3-I860N and an intermediate firing mode with Cav3.3-I860M, respectively. Such neuronal hyper-excitability could explain seizures in the patient with the p.(Ile860Asn) mutation. Thus, our study implicates CACNA1I gain-of-function mutations in neurodevelopmental disorders, with a phenotypic spectrum ranging from borderline intellectual functioning to a severe neurodevelopmental disorder with epilepsy.
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Affiliation(s)
- Yousra El Ghaleb
- Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria
| | - Pauline E Schneeberger
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| | - Monica L Fernández-Quintero
- Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria
- Institute of Theoretical Chemistry, University of Innsbruck, Innsbruck 6020, Austria
| | - Stefanie M Geisler
- Department of Pharmacology, University of Innsbruck, Innsbruck 6020, Austria
| | - Simone Pelizzari
- Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria
| | - Abeltje M Polstra
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1012 WX, The Netherlands
| | - Johanna M van Hagen
- Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, 1012 WX, The Netherlands
| | - Jonas Denecke
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| | - Marta Campiglio
- Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria
| | - Klaus R Liedl
- Institute of Theoretical Chemistry, University of Innsbruck, Innsbruck 6020, Austria
| | - Cathy A Stevens
- Department of Pediatrics, University of Tennessee College of Medicine, Chattanooga, TN 37403, USA
| | | | - Stefan Rentas
- Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Eric D Marsh
- Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Laura K Conlin
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Petronel Tuluc
- Department of Pharmacology, University of Innsbruck, Innsbruck 6020, Austria
| | - Kerstin Kutsche
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg 20251, Germany
| | - Bernhard E Flucher
- Institute of Physiology, Medical University Innsbruck, Innsbruck 6020, Austria
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Boscia F, Elkjaer ML, Illes Z, Kukley M. Altered Expression of Ion Channels in White Matter Lesions of Progressive Multiple Sclerosis: What Do We Know About Their Function? Front Cell Neurosci 2021; 15:685703. [PMID: 34276310 PMCID: PMC8282214 DOI: 10.3389/fncel.2021.685703] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 05/23/2021] [Indexed: 12/19/2022] Open
Abstract
Despite significant advances in our understanding of the pathophysiology of multiple sclerosis (MS), knowledge about contribution of individual ion channels to axonal impairment and remyelination failure in progressive MS remains incomplete. Ion channel families play a fundamental role in maintaining white matter (WM) integrity and in regulating WM activities in axons, interstitial neurons, glia, and vascular cells. Recently, transcriptomic studies have considerably increased insight into the gene expression changes that occur in diverse WM lesions and the gene expression fingerprint of specific WM cells associated with secondary progressive MS. Here, we review the ion channel genes encoding K+, Ca2+, Na+, and Cl- channels; ryanodine receptors; TRP channels; and others that are significantly and uniquely dysregulated in active, chronic active, inactive, remyelinating WM lesions, and normal-appearing WM of secondary progressive MS brain, based on recently published bulk and single-nuclei RNA-sequencing datasets. We discuss the current state of knowledge about the corresponding ion channels and their implication in the MS brain or in experimental models of MS. This comprehensive review suggests that the intense upregulation of voltage-gated Na+ channel genes in WM lesions with ongoing tissue damage may reflect the imbalance of Na+ homeostasis that is observed in progressive MS brain, while the upregulation of a large number of voltage-gated K+ channel genes may be linked to a protective response to limit neuronal excitability. In addition, the altered chloride homeostasis, revealed by the significant downregulation of voltage-gated Cl- channels in MS lesions, may contribute to an altered inhibitory neurotransmission and increased excitability.
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Affiliation(s)
- Francesca Boscia
- Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples "Federico II", Naples, Italy
| | - Maria Louise Elkjaer
- Neurology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark
| | - Zsolt Illes
- Neurology Research Unit, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.,Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.,Department of Neurology, Odense University Hospital, Odense, Denmark
| | - Maria Kukley
- Achucarro Basque Center for Neuroscience, Leioa, Spain.,Ikerbasque Basque Foundation for Science, Bilbao, Spain
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Koga S, Onishi H, Masuda S, Fujimura A, Ichimiya S, Nakayama K, Imaizumi A, Nishiyama K, Kojima M, Miyoshi K, Nakamura K, Umebayashi M, Morisaki T, Nakamura M. PTPN3 is a potential target for a new cancer immunotherapy that has a dual effect of T cell activation and direct cancer inhibition in lung neuroendocrine tumor. Transl Oncol 2021; 14:101152. [PMID: 34134073 PMCID: PMC8208899 DOI: 10.1016/j.tranon.2021.101152] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 05/25/2021] [Accepted: 06/04/2021] [Indexed: 11/30/2022] Open
Abstract
PTPN3 suppression associates with lymphocyte activation and cancer suppression. PTPN3 is involved in the induction of malignant traits. PTPN3 is associated with cellular immunosuppression. Signals from PTPN3 go through MAPK and PI3K signaling. PTPN3-inhibited lung NET cells enhance PTPN3-suppressed activated lymphocytes. In our previous study, we found that inhibition of protein tyrosine phosphatase non-receptor type 3 (PTPN3), which is expressed in lymphocytes, enhances lymphocyte activation, suggesting PTPN3 may act as an immune checkpoint molecule. However, PTPN3 is also expressed in various cancers, and the biological significance of PTPN3 in cancer cells is still not well understood, especially for lung neuroendocrine tumor (NET).Therefore, we analyzed the biological significance of PTPN3 in small cell lung cancer and examined the potential for PTPN3 inhibitory treatment as a cancer treatment approach in lung NET including small cell lung cancer (SCLC) and large cell neuroendocrine cancer (LCNEC). Experiments in a mouse xenograft model using allo lymphocytes showed that PTPN3 inhibition in SCLC cells enhanced the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In addition, PTPN3 was associated with increased vascularization, decreased CD8/FOXP3 ratio and cellular immunosuppression in SCLC clinical specimens. Experiments in a mouse xenograft model using autocrine lymphocytes also showed that PTPN3 inhibition in LCNEC cells augmented the anti-tumor effect of PTPN3-suppressed activated lymphocytes. In vitro experiments showed that PTPN3 is involved in the induction of malignant traits such as proliferation, invasion and migration. Signaling from PTPN3 is mediated by MAPK and PI3K signals via tyrosine kinase phosphorylation through CACNA1G calcium channel. Our results show that PTPN3 suppression is associated with lymphocyte activation and cancer suppression in lung NET. These results suggest that PTPN3 suppression could be a new method of cancer treatment and a major step in the development of new cancer immunotherapies.
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Affiliation(s)
- Satoko Koga
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Shogo Masuda
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Akiko Fujimura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Shu Ichimiya
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazunori Nakayama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Imaizumi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Kenichi Nishiyama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
| | - Masayuki Kojima
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
| | - Kei Miyoshi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Katsuya Nakamura
- Department of Respiratory Surgery, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu, Japan
| | | | | | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Wei Z, Liu C, Wu Z, Cao M, Qiao X, Han T, Zhang Y, Liu Y, Deng Y. The prognosis of epilepsy patients with CACNA1H missense variants: A longitudinal cohort study. Seizure 2021; 91:52-59. [PMID: 34098317 DOI: 10.1016/j.seizure.2021.05.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/19/2021] [Accepted: 05/21/2021] [Indexed: 01/05/2023] Open
Abstract
OBJECTIVE CACNA1H is regarded as a gene conferring susceptibility to generalised epilepsy. However, the prognosis of epilepsy patients carrying the CACNA1H missense variants of uncertain significance (VUS) is unknown. A prospective cohort was generated to determine the deleterious effects of these variants and to check whether the presence of these variants affects the prognosis of epilepsy patients. METHOD This study was conducted at Xijing Hospital in Xian, China. All patients were followed up for at least 1 year. Previous reports were searched for previously reported variants. Ensembl database was searched for variants in the general population. Combined Annotation Dependent Depletion (CADD) was used to evaluate the deleterious effect of variants. Logistic regression and Cox regression were used for data analysis. RESULTS The study included 176 epilepsy patients with or without CACNA1H variants. In epilepsy patients with missense variants, we found 35 different variants, including 33 variants with uncertain significance and 2 likely benign variants. No significant difference was observed between the distribution of CADD scores of the variants from this cohort, of the general population, and of those found in previous reports. Among epilepsy patients with missense variants, the number of antiepileptic drugs (AEDs) administered to the patients, a first-degree family history of epilepsy, and possibly the presence of abnormalities in brain radiology findings were correlated with the poorer prognosis. Among the entire cohort, the type of epilepsy, number of AEDs administered, and presence of abnormalities in brain radiology findings were associated with the prognosis of these patients. The deleterious effect of CACNA1H missense variants or their presence was not related to the prognosis of epilepsy patients. CONCLUSION The results of our study suggest that CACNA1H variants are related to multiple epilepsy syndromes. However, there is no strong evidence of the correlation between CACNA1H missense variants and a certain type of epilepsy. In our study cohort, both the deleterious effects and the presence of CACNA1H variants were found to be unrelated to the prognosis of patients with epilepsy. These findings suggest that CACNA1H missense variants that are classified as VUS might not influence the outcome of epilepsy.
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Affiliation(s)
- Zihan Wei
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Chao Liu
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Zhenyu Wu
- Department of Anatomy, Histology and Embryology and K.K. Leung Brain Research Centre, School of Basic Medicine, Fourth Military Medical University, Xi'an 710032, China
| | - Mi Cao
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Xiaozhi Qiao
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Tenghui Han
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Ying Zhang
- Department of Neurology, Xian International Medical Center, People's Republic of China
| | - Yonghong Liu
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China
| | - Yanchun Deng
- Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, People's Republic of China.
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Striessnig J. Voltage-Gated Ca 2+-Channel α1-Subunit de novo Missense Mutations: Gain or Loss of Function - Implications for Potential Therapies. Front Synaptic Neurosci 2021; 13:634760. [PMID: 33746731 PMCID: PMC7966529 DOI: 10.3389/fnsyn.2021.634760] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
This review summarizes our current knowledge of human disease-relevant genetic variants within the family of voltage gated Ca2+ channels. Ca2+ channelopathies cover a wide spectrum of diseases including epilepsies, autism spectrum disorders, intellectual disabilities, developmental delay, cerebellar ataxias and degeneration, severe cardiac arrhythmias, sudden cardiac death, eye disease and endocrine disorders such as congential hyperinsulinism and hyperaldosteronism. A special focus will be on the rapidly increasing number of de novo missense mutations identified in the pore-forming α1-subunits with next generation sequencing studies of well-defined patient cohorts. In contrast to likely gene disrupting mutations these can not only cause a channel loss-of-function but can also induce typical functional changes permitting enhanced channel activity and Ca2+ signaling. Such gain-of-function mutations could represent therapeutic targets for mutation-specific therapy of Ca2+-channelopathies with existing or novel Ca2+-channel inhibitors. Moreover, many pathogenic mutations affect positive charges in the voltage sensors with the potential to form gating-pore currents through voltage sensors. If confirmed in functional studies, specific blockers of gating-pore currents could also be of therapeutic interest.
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Affiliation(s)
- Jörg Striessnig
- Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria
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