Abstract
We have positionally cloned and characterized a new calcium channel auxiliary subunit, alpha(2)delta-2 (CACNA2D2), which shares 56% amino acid identity with the known alpha(2)delta-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 alpha(2)delta-2 expression is different from alpha(2)delta-1, and alpha(2)delta-2 mRNA is most abundantly expressed 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 skeletal 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 Ca(2+) currents 9-fold, and when co-expressed with alpha(1C) or alpha(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 encodes a functional auxiliary subunit of voltage-gated Ca(2+) channels. Because of its chromosomal location and expression patterns, CACNA2D2 needs to be explored as a potential tumor suppressor gene linking Ca(2+) 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.
Highlights
We have positionally cloned and characterized a new calcium channel auxiliary subunit, ␣2␦-2 (CACNA2D2), which shares 56% amino acid identity with the known ␣2␦-1 subunit
Characteristics of ␣2␦-2 cDNA and Its Predicted Amino Acid Sequence—Human chromosome 3p21.3 is deleted in many small cell lung cancers
BLAST searches and homology alignment revealed that the predicted protein shares 56% amino acid sequence identity with the human auxiliary ␣2␦-1 subunit (GenBankTM number M76559) of voltage-gated Ca2ϩ channels [13]
Summary
12237–12242, 2000 Printed in U.S.A. Functional Properties of a New Voltage-dependent Calcium Channel ␣2␦ Auxiliary Subunit Gene (CACNA2D2) *. Electrophysiological and molecular cloning studies have revealed an incredible diversity of voltage-gated calcium channels They are formed by heteromultimeric complexes of ␣1, ␣2␦, , and ␥ subunits. Co-expression studies have established two physiological roles of  subunits in high voltage-activated Ca2ϩ channels: they dramatically increase ␣1 expression at the plasma membrane, and they alter the biophysical properties of the channel currents. Function of ␣2␦-2 Voltage-dependent Calcium Channel Subunit allele loss and occasional homozygous deletions have been found in lung, breast, and other human tumors [25]. We have studied the tissue distribution of expression of this new ␣2␦-2 gene and tested the function of the gene product in Xenopus oocytes by coexpressing ␣2␦-2 cRNAs along with a representative member of the three families of calcium subunit ␣1 subunits. We find a pattern of expression different from the other ␣2␦ subunit, whereas the ␣2␦-2 enhances the activity of the calcium subunit ␣1 subunits
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