Functional biology of the α2δ subunits of voltage-gated calcium channels

In this review, we examine what is known about the mechanism of action of the auxiliary α2δ subunits of voltage-gated Ca2+ (Cav) channels. First, to provide some background on the α2δ proteins, we discuss the genes encoding these channels, in addition to the topology and predicted structure of the α2δ subunits. We then describe the effects of α2δ subunits on the biophysical properties of Cav channels and their physiological function. All α2δ subunits increase the density at the plasma membrane of Ca2+ channels activated by high voltage, and we discuss what is known about the mechanism underlying this trafficking. Finally, we consider the link between α2δ subunits and disease, both in terms of spontaneous and engineered mouse mutants that show cerebellar ataxia and spike-wave epilepsy, and in terms of neuropathic pain and the mechanism of action of the gabapentinoid drugs – small-molecule ligands of the α2δ-1 and α2δ-2 subunits.