Functional properties of a new voltage-dependent calcium channel auxiliary subunit gene (CACNA2D2)

We have positionally cloned and characterized a new calcium channel auxiliary subunit, α₂δ-2 (CACNA2D2), which shares 56% amino acid identity with the known α₂δ-1 subunit. The gene maps to the critical human tumor suppressor gene region in chromosome 3p21.3, showing very frequent allele loss and occasional homozygous deletions in lung, breast, and other cancers. The tissue distribution of α₂δ-2 expression is different from α₂δ-1, and α₂δ-2 mRNA is most abundantly expressed in lung and testis and well expressed in brain, heart, and pancreas. In contrast, α₂δ-1 is expressed predominantly in brain, heart, and skeletal muscle. When co-expressed (via cRNA injections) with α(1B) and β₃ subunits in Xenopus oocytes, α₂δ-2 increased peak size of the N-type Ca²⁺ currents 9-fold, and when co- expressed with α(1C) or α(1G) subunits in Xenopus oocytes increased peak size of L-type channels 2-fold and T-type channels 1.8-fold, respectively. Anti-peptide antibodies detect the expression of a 129-kDa α₂δ-2 polypeptide in some but not all lung tumor cells. We conclude that the α₂δ-2 gene encodes a functional auxiliary subunit of voltage-gated Ca²⁺ channels. Because of its chromosomal location and expression patterns, CACNA2D2 needs to be explored as a potential tumor suppressor gene linking Ca²⁺ signaling and lung, breast, and other cancer pathogenesis. The homologous location on mouse chromosome 9 is also the site of the mouse neurologic mutant ducky (du), and thus, CACNA2D2 is also a candidate gene for this inherited idiopathic generalized epilepsy syndrome.