Emerging evidence for specific neuronal functions of auxiliary calcium channel α₂δ subunits

In nerve cells the ubiquitous second messenger calcium regulates a variety of vitally important functions including neurotransmitter release, gene regulation, and neuronal plasticity. The entry of calcium into cells is tightly regulated by voltage-gated calcium channels, which consist of a heteromultimeric complex of a pore forming α₁, and the auxiliary β and α₂δ subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached α₂δ subunits (α₂δ-1 to α₂δ-4), out of which three isoforms (α₂δ-1 to -3) are strongly expressed in the central nervous system. Over the years a wealth of studies has demonstrated the classical role of α₂δ subunits in channel trafficking and calcium current modulation. Recent studies in specialized neuronal cell systems propose roles of α₂δ subunits beyond the classical view and implicate α₂δ subunits as important regulators of synapse formation. These findings are supported by the identification of novel human disease mutations associated with α₂δ subunits and by the fact that α₂δ subunits are the target of the anti-epileptic and anti-allodynic drugs gabapentin and pregabalin. Here we review the recently emerging evidence for specific as well as redundant neuronal roles of α₂δ subunits and discuss the mechanisms for establishing and maintaining specificity.