Voltage-dependent Ca2+ channel alpha2delta auxiliary subunit: structure, function and regulation.

Voltage-dependent Ca2+ channels are heteromultimeric proteins consisting minimally of a alpha1 main subunit and auxiliary alpha2delta, and beta subunits. The alpha1 subunit forms the ion-conducting pore and contains receptor sites for ligands that modify channel activity. The auxiliary subunits appear to be necessary for the expression of the native kinetic properties of the channel. In particular, the alpha2delta complex, with the transmembrane domain-containing delta subunit arising as a result of proteolysis from the C-terminal end of a alpha2delta precursor, has shown to modify the biophysical and pharmacological properties of the alpha1 subunit in different model systems. Structure-function studies have provided insight into the molecular mechanisms through which alpha2delta exerts its actions and revealed that both allosteric modulation and cellular localization of the Ca2+ channel complex are important mechanisms for alpha2delta regulation of ionic current. Recent studies have shown that the alpha2delta subunit can also support pharmacological interactions with therapeutic agents for the treatment of neurological disorders.