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Functional Expression and Characterization of a Voltage-Gated Ca_V1.3 (_1D) Calcium Channel Subunit from an Insulin-Secreting Cell Line

Institut für Pharmakologie (A.S., T.D.P., B.N.) Freie Universität Berlin 14195 Berlin, Germany
Department of Pharmacology University College London (A.C.D.) WC1E 6BT, United Kingdom
Abteilung für Pharmakologie und Toxikologie (B.N.) Universität Ulm 89081 Ulm, Germany

L-type calcium channels mediate depolarization-induced calcium influx in insulin-secreting cells and are thought to be modulated by G protein-coupled receptors (GPCRs). The major fraction of L-type ₁-subunits in pancreatic ß-cells is of the neuroendocrine subtype (Ca_V1.3 or _1D). Here we studied the biophysical properties and receptor regulation of a Ca_V1.3 subunit previously cloned from HIT-T15 cells. In doing so, we compared this neuroendocrine Ca_V1.3 channel with the cardiac L-type channel Ca_V1.2a (or _1C-a) after expression together with ₂- and ß₃-subunits in Xenopus oocytes. Both the current voltage relation and voltage dependence of inactivation for the neuroendocrine Ca_V1.3 channel were shifted to more negative potentials compared with the cardiac Ca_V1.2 channel. In addition, the Ca_V1.3 channel activated and inactivated more rapidly than the Ca_V1.2a channel. Both subtypes showed a similar sensitivity to the dihydropyridine (+)isradipine. More interestingly, the Ca_V1.3 channels were found to be stimulated by ligand-bound G_i/G_o-coupled GPCRs whereas a neuronal Ca_V2.2 (or _1B) channel was inhibited. The observed receptor-induced stimulation of Ca_V1.3 channels could be mimicked by phorbol-12-myristate-13-acetate and was sensitive to inhibitors of protein kinases, but not to the phosphoinositol-3-kinase-inhibitor wortmannin, pointing to serine/threonine kinase-dependent regulation. Taken together, we describe a neuroendocrine L-type Ca_V1.3 calcium channel that is stimulated by G_i/G_o-coupled GPCRs and differs significantly in distinct biophysical characteristics from the cardiac subtype (Ca_V1.2a), suggesting that the channels have different roles in native cells.

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