Role of voltage-gated calcium channels in epilepsy.
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 alpha1 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.
Zamponi
Gerald W
GW
Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, T2N 4N1, Canada.
Lory
Philippe
P
Perez-Reyes
Edward
E
D000818:Animals; D020864:Calcium Channels, N-Type / Q000502:physiology*; D020747:Calcium Channels, T-Type / Q000235:genetics* / Q000502:physiology; D004827:Epilepsy / Q000503:physiopathology*; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D021122:Protein Subunits / Q000235:genetics
D020864:Calcium Channels, N-Type; D020747:Calcium Channels, T-Type; D021122:Protein Subunits; C479952:CACNA1H protein, human