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The Journal of Neuroscience, October 1, 2000, 20(19):7167-7173

Muscarinic Stimulation of 1E Ca Channels Is Selectively Blocked by the Effector Antagonist Function of RGS2 and Phospholipase C-1

Karim Melliti¹, Ulises Meza², and Brett Adams¹

¹ Department of Biology, Utah State University, Logan, Utah 84322-5305, and ² Department of Physiology and Pharmacology, College of Medicine, Autonomous University of San Luis Potosí, SLP 78210, México

Neuronal 1E Ca channel subunits are widely expressed in mammalian brain, where they are thought to form R-type Ca channels. Recent studies have demonstrated that R-type channels contribute to neurosecretion and dendritic Ca influx, but little is known concerning their modulation. Here we show that 1E channels are strongly stimulated, and only weakly inhibited, through M1 muscarinic acetylcholine receptors. Both forms of channel modulation are mediated by pertussis toxin-insensitive G-proteins. Channel stimulation is blocked by regulator of G-protein signaling 2 (RGS2) or the C-terminal region of phospholipase C-1 (PLC1ct), which have been previously shown to function as GTPase-activating proteins for Gq. In contrast, RGS2 and PLC1ct do not block inhibition of 1E through M1 receptors. Inhibition is prevented, however, by the C-terminal region of -adrenergic receptor kinase 1, which sequesters G dimers. Thus, stimulation of 1E is mediated by a pertussis toxin-insensitive G subunit (e.g., Gq), whereas inhibition is mediated by G. The ability of RGS2 and PLC1ct to selectively block stimulation indicates these proteins functioned primarily as effector antagonists. In support of this interpretation, RGS2 prevented stimulation of 1E with non-hydrolyzable guanosine 5'-0-(3-thiotriphosphate). We also report strong muscarinic stimulation of rbE-II, a variant 1E Ca channel that is insensitive to voltage-dependent inhibition. Our results predict that Gq-coupled receptors predominantly stimulate native R-type Ca channels. Receptor-mediated enhancement of R-type Ca currents may have important consequences for neurosecretion, dendritic excitability, gene expression, or other neuronal functions.

Key words: Ca_V2.3; R-type calcium channel; 1E; RGS protein; phospholipase C-1; GAP; effector antagonist

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20197167-07$05.00/0

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