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J. Biol. Chem., Vol. 279, Issue 15, 14619-14630, April 9, 2004

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Ca²⁺ and Phosphatidylinositol 4,5-Bisphosphate Stabilize a G-sensitive State of Ca_V2 Ca²⁺ Channels^*

Matthieu Rousset, Thierry Cens, Annie Gouin-Charnet¶, Frédérique Scamps||, and Pierre Charnet**

From the Centre de Recherche de Biochimie Macromoléculaire, CNRS-FRE 2593, 1919 Route de Mende, 34293 Montpellier, ^¶Centre CNRS-INSERM de Pharmacologie-Endocrinologie U469, rue de la Cardonille, 34094 Montpellier, and ^||INSERM U583, Place Eugène Bataillon, 34095 Montpellier, France

Direct interactions between G-protein subunits and N- or P/Q-type Ca²⁺ channels mediate the inhibitory action of several neurotransmitters in the brain. Membrane potential, channel phosphorylation, or auxiliary subunit association tightly regulate these interactions and the consequent inhibition of Ca²⁺ current. We now provide evidence that intracellular Ca²⁺ concentration and phosphoinositides play a stabilizing role in this direct voltage-dependent inhibition. Lowering resting cytosolic Ca²⁺ concentration in Xenopus oocytes expressing Ca_V2Ca²⁺ channels strongly decreased basal as well as phasic, agonist-dependent inhibition of Ca²⁺ channels by G-proteins. Decreasing phosphoinositide levels also suppressed G-protein inhibition and completely occluded the effects of a subsequent injection of Ca²⁺ chelator. Similar regulations are observed in mouse dorsal root ganglia neurons. Alteration of G-protein block by these agents is independent of protein phosphorylation, cytoskeleton dynamics, and GTPase or GDP/GTP exchange activity, suggesting a direct action at the level of the Ca²⁺ channel/G-protein interaction. Moreover, affinity binding experiments of intracellular loops of the Ca_V2.1 Ca²⁺ channels to different phospholipids revealed specific interactions between the C-terminal tail of the channel and phosphoinositides. Taken together these data indicate that a Ca²⁺-sensitive interaction of the C-terminal tail of P/Q channels with the plasma membrane is important for G-protein regulation.

Received for publication, December 5, 2003 , and in revised form, January 7, 2004.

^* This work was supported by Association Française contre les Myopathies, Association pour la Recherche contre le Cancer, and the Fondation Simone Cino Del Duca. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental material.

Supported by the Fondation pour la Recherche Médicale and French Ministry of Education.

^** To whom correspondence should be addressed. E-mail: charnet{at}crbm.cnrs-mop.fr.

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