Role of voltage-gated calcium channels in epilepsy

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 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.

Figure 1. Voltage-gated calcium channels (VGCCs): naming and structure

A. Dendrogram illustrating the three subfamilies of VGCCs: the Ca_v1 (L-types), the Ca_v2 (neuronal types), and the Ca_v3 (T-types). Ca_v1 and Ca_v2 channels are high-voltage activated (HVA), in contrast to Ca_v3 channels (T-types), which are low-voltage activated (LVA). B. The molecular structure of HVA channels comprises ancillary subunits α₂δ, β, and γ, each encoded by several subunits. In contrast, the subunit composition of LVA/T-type channels is not yet resolved.

Figure 2. Mutations in P/Q-type calcium channels in mouse (A) and humans (B)

A. Schematic representation of the multiple mutations that affect the various subunits of the P/Q-type calcium channels in mouse and the corresponding mouse phenotypes. b Location of mutations in human P/Q-type α1 subunits that related to episodic ataxia type 2 (EA2), familial hemiplegic migraine type 1 (FHM1), spinocerebellar ataxia type 6 (SCA6), as well as more complex clinical patterns such as progressive ataxia with absence epilepsy (red squares) are indicated.

Figure 3. Variants of Ca_v3.2

Location of IGE variants are mapped on a scaled model of Ca_v3.2 (each ball represents an amino acid). Key: red balls, IGE variants reported by Chen et al., [21] and Heron et al., [37]; orange ball, the GAERS variant [66]; pink balls, TLE variants [37]; and green, the common SNP, R788C. A frame-shift mutation, V621fsX654, was found in patients with febrile seizures, which leads to premature truncation of the protein at a.a. residue 654 [37].