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Cited by 53Neuroscience and Neuropharmacology ResearchIon channel regulation and functionEpilepsy research and treatment

CaV3.2 calcium channels control NMDA receptor-mediated transmission: a new mechanism for absence epilepsy

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Wang, Guangfu, Bochorishvili, Genrieta, Chen, Yucai, Salvati, Kathryn A., Zhang, Peng, Dubel, Steve J., Perez-Reyes, Edward, Snutch, Terrance P. +8 more·2015·Genes & Development
DOI 10.1101/gad.260869.115PMC PMC4526737
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Abstract

Ca V 3.2 T-type calcium channels, encoded by CACNA1H, are expressed throughout the brain, yet their general function remains unclear. We discovered that Ca V 3.2 channels control NMDA-sensitive glutamatergic receptor (NMDA-R)-mediated transmission and subsequent NMDA-R-dependent plasticity of AMPA-R-mediated transmission at rat central synapses. Interestingly, functional Ca V 3.2 channels primarily incorporate into synapses, replace existing Ca V 3.2 channels, and can induce local calcium influx to control NMDA transmission strength in an activity-dependent manner. Moreover, human childhood absence epilepsy (CAE)-linked hCa V 3.2(C456S) mutant channels have a higher channel open probability, induce more calcium influx, and enhance glutamatergic transmission. Remarkably, cortical expression of hCa V 3.2(C456S) channels in rats induces 2- to 4-Hz spike and wave discharges and absence-like epilepsy characteristic of CAE patients, which can be suppressed by AMPA-R and NMDA-R antagonists but not T-type calcium channel antagonists. These results reveal an unexpected role of Ca V 3.2 channels in regulating NMDA-R-mediated transmission and a novel epileptogenic mechanism for human CAE.

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Authors
Wang, G., Bochorishvili, G., Chen, Y., Salvati, K. A., Zhang, P., Dubel, S. J., Perez-Reyes, E., Snutch, T. P., Stornetta, R. L., Deisseroth, K., Erisir, A., Todorovic, S. M., Luo, J.-H., Kapur, J., Beenhakker, M. P., & Zhu, J. J.
Affiliations
  • University of Virginia (US)
  • Centre National de la Recherche Scientifique (FR)
  • University of British Columbia (CA)
  • Howard Hughes Medical Institute (US)
ORCID
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2015-07-15
Volume
29
Issue
14
Pages
1535-1551
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.260869.115
PMC
PMC4526737
OpenAlex
W1893862769
Cited by
53
References
7
Citations by year
2026: 2 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 6 · 2021: 2 · 2020: 4 · 2019: 6 · 2018: 5 · 2017: 9 · 2016: 7
Type
posted content
Language
en
Open access
Licence
cc-by-nc
Locations
  • Genes & Development (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (R01NS053570, R01NS091452, R01NS067456, R01GM102525, R01NS040337, R01DC010183)
  • Epilepsy Foundation (310443)
  • Howard Hughes Medical Institute
  • National Basic Research Program of China (2010CB912002)
  • Natural Science Foundation of China (30730038, 81171164)
  • Canadian Institutes of Health Research (10677)
  • Canada Research Chair in Biotechnology and Genomics-Neurology
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
Keywords
Cav3.2 T-type calcium channel, CACNA1H, childhood absence epilepsy, spike-wave discharges, glutamatergic synapses, epileptogenic mechanisms, AMPA receptor antagonists, NMDA receptor antagonists
MeSH terms
Animals, Calcium Channel Blockers, Epilepsy, Absence, Gene Expression Regulation, Humans, Mutation, Recombinant Proteins, Synapses, Calcium Channels, Signal Transduction, Receptors, N-Methyl-D-Aspartate, Calcium Channels, T-Type, Rats

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