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 alpha(1), and the auxiliary beta and alpha(2)delta subunits. Four genes (Cacna2d1-4) encode for the extracellular membrane-attached alpha(2)delta subunits (alpha(2)delta-1 to alpha(2)delta-4), out of which three isoforms (alpha(2)delta-1 to -3) are strongly expressed in the central nervous system. Over the years a wealth of studies has demonstrated the classical role of alpha(2)delta subunits in channel trafficking and calcium current modulation. Recent studies in specialized neuronal cell systems propose roles of alpha(2)delta subunits beyond the classical view and implicate alpha(2)delta subunits as important regulators of synapse formation. These findings are supported by the identification of novel human disease mutations associated with alpha(2)delta subunits and by the fact that alpha(2)delta 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 alpha(2)delta subunits and discuss the mechanisms for establishing and maintaining specificity