Calcium channel α2δ subunits:: Differential expression, function, and drug binding

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 alpha(1) subunit and auxiliary alpha(2)delta, beta, and - in some tissues - gamma subunits. Auxiliary subunits support the membrane trafficking of the alpha(1) subunit and modulate the kinetic properties of the channel. In particular, the alpha(2)delta subunit has been shown to modify the biophysical and pharmacological properties of the alpha(1) subunit. The alpha(2)delta subunit is posttranslationally cleaved to form disulfide-linked alpha(2) and, delta proteins, both of which are heavily glycosylated. Recently it was shown that at least four genes encode for alpha(2)delta 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 alpha(2)delta-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. alpha(2)delta subunits can also support pharmacological interactions with drugs that are used for the treatment of epilepsy and neuropathic pain.