The α2δ subunit augments functional expression and modifies the pharmacology of CaV1.3 L-type channels

The auxiliary Ca-V alpha(2)delta-1 subunit is an important component of voltage-gated Ca2+ (Ca-V) channel complexes in many tissues and of great interest as a drug target. Nevertheless, its exact role in specific cell functions is still unknown. This is particularly important in the case of the neuronal L-type Ca-V channels where these proteins play a key role in the secretion of neurotransmitters and hormones, gene expression, and the activation of other ion channels. Therefore, using a combined approach of patch-clamp recordings and molecular biology, we studied the role of the Ca-V alpha(2)delta-1 subunit on the functional expression and the pharmacology of recombinant L-type Ca(V)1.3 channels in HEK-293 cells. Co-expression of Ca-V alpha(2)delta-1 significantly increased macroscopic currents and conferred the Ca(V)1.3 alpha(1)/Ca-V beta(3) channels sensitivity to the antiepileptic/analgesic drugs gabapentin and AdGABA. In contrast, Ca-V alpha(2)delta-1 subunits harboring point mutations in N-glycosylation consensus sequences or the proteolytic site as well as in conserved cysteines in the transmembrane delta domain of the protein, reduced functionality in terms of enhancement of Ca(V)1.3 alpha(1)/Ca-V beta(3) currents. In addition, co-expression of the delta domain drastically inhibited macroscopic currents through recombinant Ca(V)1.3 channels possibly by affecting channel synthesis. Together these results provide several lines of evidence that the Ca-V alpha(2)delta-1 auxiliary subunit may interact with Ca(V)1.3 channels and regulate their functional expression. (c) 2009 Elsevier Ltd. All rights reserved.