Functional properties of a new voltage-dependent calcium channel alpha(2)delta auxiliary subunit gene (CACNA2D2)

We have positionally cloned and characterized a new calcium channel auxilia ry subunit, alpha(2)delta-2 (CACNA2D2), which shares 56% amino acid identit y with the known alpha(2)delta-1 subunit. The gene maps to the critical hum an 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 alpha(2)delta-2 expression is differen t from alpha(2)delta-1, and alpha(2)delta-2 mRNA is most abundantly express ed in lung and testis and well expressed in brain, heart, and pancreas. In contrast, alpha(2)delta-1 is expressed predominantly in brain, heart, and s keletal muscle. When co-expressed (via cRNA injections) with alpha(1B) and beta(3) subunits in Xenopus oocytes, alpha(2)delta-2 increased peak size of the N-type Ca2+ currents 9-fold, and when co-expressed with alpha(1C) or a lpha(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 alpha(2)delta-2 polypeptide in some but not all lung tumor cells, We conclude that the alpha(2)delta-2 gene encode s a functional auxiliary subunit of voltage-gated Ca2+ channels. Because of its chromosomal location and expression patterns, CACNA2D2 needs to be exp lored as a potential tumor suppressor gene linking Ca2+ signaling and lung, breast, and other cancer pathogenesis. The homologous location on mouse ch romosome 9 is also the site of the mouse neurologic mutant ducky (du), and thus, CACNA2D2 is also a candidate gene for this inherited idiopathic gener alized epilepsy syndrome.