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J. Biol. Chem., Vol. 282, Issue 29, 21043-21055, July 20, 2007

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Selective Inhibition of Cav3.3 T-type Calcium Channels by G_q/11-coupled Muscarinic Acetylcholine Receptors^*

Michael E. Hildebrand, Laurence S. David, Jawed Hamid, Kirk Mulatz, Esperanza Garcia, Gerald W. Zamponi, and Terrance P. Snutch¹

From the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4 and the Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta T2N 4N1, Canada

T-type calcium channels play critical roles in controlling neuronal excitability, including the generation of complex spiking patterns and the modulation of synaptic plasticity, although the mechanisms and extent to which T-type Ca²⁺ channels are modulated by G-protein-coupled receptors (GPCRs) remain largely unexplored. To examine specific interactions between T-type Ca²⁺ channel subtypes and muscarinic acetylcholine receptors (mAChRS), the Cav3.1 (_1G), Cav3.2 (_1H), and Cav3.3 () T-type Ca²⁺_1Ichannels were co-expressed with the M1 G_q/11-coupled mAChR. Perforated patch recordings demonstrate that activation of M1 receptors has a strong inhibitory effect on Cav3.3 T-type Ca²⁺ currents but either no effect or a moderate stimulating effect on Cav3.1 and Cav3.2 peak current amplitudes. This differential modulation was observed for both rat and human T-type Ca²⁺ channel variants. The inhibition of Cav3.3 channels by M1 receptors is reversible, use-independent, and associated with a concomitant increase in inactivation kinetics. Loss-of-function experiments with genetically encoded antagonists of G and G proteins and gain-of-function experiments with genetically encoded G subtypes indicate that M1 receptor-mediated inhibition of Cav3.3 occurs through G_q/11. This is supported by experiments showing that activation of the M3 and M5 G_q/11-coupled mAChRs also causes inhibition of Cav3.3 currents, although G_i-coupled mAChRs (M2 and M4) have no effect. Examining Cav3.1-Cav3.3 chimeric channels demonstrates that two distinct regions of the Cav3.3 channel are necessary and sufficient for complete M1 receptor-mediated channel inhibition and represent novel sites not previously implicated in T-type channel modulation.

Received for publication, December 26, 2006 , and in revised form, April 19, 2007.

^* This work was supported in part by operating grants from the Canadian Institutes for Health Research and Canada Research Tier 1 Chairs (to T. P. S. and G. W. Z.) a fellowship from the Heart and Stroke Foundation of Canada, and trainee fellowships from the Natural Sciences and Engineering Research Council of Canada and Michael Smith Foundation for Health Research (to M. E. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Michael Smith Laboratories, University of British Columbia, 2185 East Mall, Vancouver, British Columbia V6T 1Z4, Canada. Tel.: 604-822-6968; Fax: 604-822-6470; E-mail: snutch{at}msl.ubc.ca.

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