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Role of voltage-gated calcium channels in epilepsy

  • Neuroscience
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Abstract

It is well established that idiopathic generalized epilepsies (IGEs) show a polygenic origin and may arise from dysfunction of various types of voltage- and ligand-gated ion channels. There is an increasing body of literature implicating both high- and low-voltage-activated (HVA and LVA) calcium channels and their ancillary subunits in IGEs. Cav2.1 (P/Q-type) calcium channels control synaptic transmission at presynaptic nerve terminals, and mutations in the gene encoding the Cav2.1 α1 subunit (CACNA1A) have been linked to absence seizures in both humans and rodents. Similarly, mutations and loss of function mutations in ancillary HVA calcium channel subunits known to co-assemble with Cav2.1 result in IGE phenotypes in mice. It is important to note that in all these mouse models with mutations in HVA subunits, there is a compensatory increase in thalamic LVA currents which likely leads to the seizure phenotype. In fact, gain-of-function mutations have been identified in Cav3.2 (an LVA or T-type calcium channel encoded by the CACNA1H gene) in patients with congenital forms of IGEs, consistent with increased excitability of neurons as a result of enhanced T-type channel function. In this paper, we provide a broad overview of the roles of voltage-gated calcium channels, their mutations, and how they might contribute to the river that terminates in epilepsy.

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Acknowledgments

GWZ is a Scientist of the Alberta Heritage Foundation for Medical Research and a Canada Research Chair in Molecular Neurobiology. PL is supported by CNRS and grants from ANR (ANR-2006-Neuro35) and Fédération pour la Recherche sur le Cerveau. EPR is supported by grants from NIH (NS067456).

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  1. Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, T2N 4N1, Canada

    Gerald W. Zamponi

  2. Département de Physiologie, Institut de Génomique Fonctionnelle, CNRS UMR 5203, INSERM U661, Université de Montpellier 1 et 2, 34094, Montpellier, France

    Philippe Lory

  3. Department of Pharmacology and Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, 22908, USA

    Edward Perez-Reyes

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Zamponi, G.W., Lory, P. & Perez-Reyes, E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch - Eur J Physiol 460, 395–403 (2010). https://doi.org/10.1007/s00424-009-0772-x

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