Functional expression and characterization of a voltage-gated Ca(v)1,3 (alpha(1D)) calcium channel subunit from an insulin-secreting cell line

L-type calcium channels mediate depolarization-induced calcium influx in in sulin-secreting cells and are thought to be modulated by G protein-coupled receptors (GPCRs). The major fraction of L-type alpha (1)-subunits in pancr eatic beta -cells is of the neuroendocrine subtype (Ca(v)1.3 or alpha (1D)) . Here we studied the biophysical properties and receptor regulation of a C a(v)1.3 subunit previously cloned from HIT-T15 cells. In doing so, we compa red this neuroendocrine Ca(v)1.3 channel with the cardiac L-type channel Ca (v)1.2a (or alpha (1C-a)) after expression together with alpha (2)delta- an d beta (3)-subunits in Xenopus oocytes. Both the current voltage relation a nd voltage dependence of inactivation for the neuroendocrine Ca(v)1.3 chann el were shifted to more negative potentials compared with the cardiac Ca(v) 1.2 channel. In addition, the Ca(v)1.3 channel activated and inactivated mo re rapidly than the Ca(v)1.2a channel. Both subtypes showed a similar sensi tivity to the dihydropyridine (+)isradipine. More interestingly, the Ca(v)1 .3 channels were found to be stimulated by ligand-bound G(1)/G(0)-coupled G PCRs whereas a neuronal Ca(v)2.2 (or alpha (1B) ) channel was inhibited. Th e observed receptor-induced stimulation of Ca(v)1.3 channels could be mimic ked by phorbol-12-myristate-13-acetate and was sensitive to inhibitors of p rotein kinases, but not to the phosphoinositol-3-kinase-inhibitor wortmanni n, pointing to serine/ threonine kinase-dependent regulation. Taken togethe r, we describe a neuroendocrine L-type Ca(v)1.3 calcium channel that is sti mulated by G(1)/G(0)-coupled GPCRs and differs significantly in distinct bi ophysical characteristics from the cardiac subtype (Ca(v)1.2a), suggesting that the channels have different roles in native cells.