Calcium Channel α2 Subunits: Differential Expression, Function, and Drug Binding

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Abstract
Voltage-activated calcium channels are transmembrane proteins that act as transducers of electrical signals into numerous intracellular activities. On the basis of their electrophysiological properties they are classified as high- and low-voltage-activated calcium channels. High-voltage-activated calcium channels are heterooligomeric proteins consisting of a pore-forming α1 subunit and auxiliary α2δ, β, and—in some tissues—γ subunits. Auxiliary subunits support the membrane trafficking of the α1 subunit and modulate the kinetic properties of the channel. In particular, the α2δ subunit has been shown to modify the biophysical and pharmacological properties of the α1 subunit. The α2δ subunit is posttranslationally cleaved to form disulfide-linked α2 and, δ proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for α2δ subunits which are expressed in a tissue-specific manner. Their biophysical properties were characterized in coexpression studies with high- and low-voltage-activated calcium channels. Mutations in the gene encoding α2δ-2 have been found to underlie the ducky phenotype. This mouse mutant is a model for absence epilepsy and is characterized by spike wave seizures and cerebellar ataxia. α2δ subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.