Abstract：
:CaV2.3 subunits are expressed in neuronal and neuroendocrine cells where they are believed to form native R-type Ca2+ channels. Although R-type currents are involved in triggering neurotransmitter and hormone secretion, little is known about their modulation. Previous studies have shown that muscarinic acetylcholine receptors evoke both inhibition and stimulation of CaV2.3. Muscarinic inhibition of CaV2.3 is mediated by Gbetagamma subunits, whereas stimulation is mediated by pertussis toxin-insensitive Galpha subunits. In the present study, we compared modulation of CaV2.3 by the three Galphaq/11-coupled muscarinic receptors (M1, M3, and M5). Our data indicate that these receptors trigger comparable stimulation of CaV2.3. The signaling pathway that mediates stimulation was meticulously analyzed for M1 receptors. Stimulation is blocked by neutralizing antibodies directed against Galphaq/11, coexpression of the regulatory domain of protein kinase Cdelta (PKCdelta), preactivating PKC with phorbol ester, or pharmacological suppression of PKC with bisindolylmaleimide I. Stimulation of CaV2.3 is Ca(2+)-independent and insensitive to 12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole (Gö 6976), a specific inhibitor of Ca(2+)-dependent PKC isozymes. These results indicate that muscarinic stimulation of CaV2.3 involves signaling by Galphaq/11, diacylglycerol, and a Ca(2+)-independent PKC. In contrast to stimulation, the magnitude of CaV2.3 inhibition depended on receptor subtype, with M3 and M5 receptors producing much larger CaV2.3 inhibition than M1 receptors. Interestingly, muscarinic inhibition of CaV2.3 was notably enhanced during pharmacological suppression of PKC, suggesting the presence of cross-talk between Gbetagamma-mediated inhibition and PKC-mediated stimulation of R-type channels similar to that described previously for N-type channels.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Bannister RA,Melliti K,Adams BAdoi
10.1124/mol.65.2.381keywords:
subject
Has Abstractpub_date
2004-02-01 00:00:00pages
381-8issue
2eissn
0026-895Xissn
1521-0111pii
65/2/381journal_volume
65pub_type
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