The Role of Calcium Channels in Epilepsy

Abstract

A central theme in the quest to unravel the genetic basis of epilepsy has been the effort to elucidate the roles played by inherited defects in ion channels. The ubiquitous expression of voltage-gated calcium channels (VGCCs) throughout the central nervous system (CNS), along with their involvement in fundamental processes, such as neuronal excitability and synaptic transmission, has made them attractive candidates. Recent insights provided by the identification of mutations in the P/Q-type calcium channel in humans and rodents with epilepsy and the finding of thalamic T-type calcium channel dysfunction in the absence of seizures have raised expectations of a causal role of calcium channels in the polygenic inheritance of idiopathic epilepsy. In this review, we consider how genetic variation in neuronal VGCCs may influence the development of epilepsy.

Figure 1.

Structure and function of voltage-gated calcium channels (VGCCs). (A) Membrane topology of the α1 subunit. The subunit consists of four domains (I–IV), each containing six transmembrane segments (S1–S6). The S4 segment of each domain is lined with positively charged amino acids and acts as the voltage sensor. The S5–S6 interlinker lines the pore of the channel. (B) Schematic of the channel complex for high-voltage-activated (HVA) and low-voltage-activated (LVA) calcium channels and their diverse biological roles. HVA channels consist of a principal α1 subunit, which forms the channel pore, a β subunit, which is cytoplasmic, an extracellular α2δ subunit, which is attached to the membrane via a glycophosphatidylinositol (GPI) anchor, and possibly a γ subunit. Alternative splicing gives rise to multiple isoforms of all the subunits. LVA channels do not appear to associate with accessory subunits. CaM, Calmodulin.