Differential Modulation of CaV2.3 Ca 2 Channels by

CaV2.3 subunits are expressed in neuronal and neuroendocrine cells where they are believed to form native R-type Ca2 chan-nels. Although R-type currents are involved in triggering neu-rotransmitter and hormone secretion, little is known about their modulation. Previous studies have shown that muscarinic ace-tylcholine receptors evoke both inhibition and stimulation of CaV2.3. Muscarinic inhibition of CaV2.3 is mediated by G subunits, whereas stimulation is mediated by pertussis toxin-insensitive G subunits. In the present study, we compared modulation of CaV2.3 by the three Gq/11-coupled muscarinic receptors (M1, M3, and M5). Our data indicate that these re-ceptors trigger comparable stimulation of CaV2.3. The signaling pathway that mediates stimulation was meticulously analyzed for M1 receptors. Stimulation is blocked by neutralizing anti-bodies directed against Gq/11, coexpression of the regulatory domain of protein kinase C (PKC), preactivating PKC with phorbol ester, or pharmacological suppression of PKC wit