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Differential Modulation of Ca_V2.3 Ca²⁺ Channels by Gq/11-Coupled Muscarinic Receptors

Department of Biology, Utah State University, Logan, Utah

Ca_V2.3 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 Ca_V2.3. Muscarinic inhibition of Ca_V2.3 is mediated by G subunits, whereas stimulation is mediated by pertussis toxin-insensitive G subunits. In the present study, we compared modulation of Ca_V2.3 by the three Gq/11-coupled muscarinic receptors (M1, M3, and M5). Our data indicate that these receptors trigger comparable stimulation of Ca_V2.3. The signaling pathway that mediates stimulation was meticulously analyzed for M1 receptors. Stimulation is blocked by neutralizing antibodies directed against Gq/11, coexpression of the regulatory domain of protein kinase C (PKC), preactivating PKC with phorbol ester, or pharmacological suppression of PKC with bisindolylmaleimide I. Stimulation of Ca_V2.3 is Ca²⁺-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 Ca²⁺-dependent PKC isozymes. These results indicate that muscarinic stimulation of Ca_V2.3 involves signaling by Gq/11, diacylglycerol, and a Ca²⁺-independent PKC. In contrast to stimulation, the magnitude of Ca_V2.3 inhibition depended on receptor subtype, with M3 and M5 receptors producing much larger Ca_V2.3 inhibition than M1 receptors. Interestingly, muscarinic inhibition of Ca_V2.3 was notably enhanced during pharmacological suppression of PKC, suggesting the presence of cross-talk between G-mediated inhibition and PKC-mediated stimulation of R-type channels similar to that described previously for N-type channels.

Received June 6, 2003; accepted October 31, 2003.

Address correspondence to: Dr. Brett Adams, Department of Biology, Utah State University, 5305 Old Main Hill, Logan, Utah 84322. E-mail: brett{at}biology.usu.edu

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