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J. Biol. Chem., Vol. 282, Issue 4, 2314-2323, January 26, 2007

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Chemical Determinants Involved in Anandamide-induced Inhibition of T-type Calcium Channels^*

From the Département de Physiologie, Institut de Génomique Fonctionnelle (IGF), CNRS UMR 5203-INSERM U661, Universités de Montpellier I and II, 141 rue de la Cardonille, 34094 Montpellier, France

Anandamide, originally described as an endocannabinoid, is the main representative molecule of a new class of signaling lipids including endocannabinoids and N-acyl-related molecules, eicosanoids, and fatty acids. Bioactive lipids regulate neuronal excitability by acting on G-protein-coupled receptors (such as CB1) but also directly modulate various ionic conductances including voltage-activated T-type calcium channels (T-channels). However, little is known about the properties and the specificity of this new class of molecules on their various targets. In this study, we have investigated the chemical determinants involved in anandamide-induced inhibition of the three cloned T-channels: Ca_V3.1, Ca_V3.2, and Ca_V3.3. We show that both the hydroxyl group and the alkyl chain of anandamide are key determinants of its effects on T-currents. As follows, T-currents are also inhibited by fatty acids. Inhibition of the three Ca_V3 currents by anandamide and arachidonic acid does not involve enzymatic metabolism and occurs in cell-free inside-out patches. Inhibition of T-currents by fatty acids and N-acyl ethanolamides depends on the degree of unsaturation but not on the alkyl chain length and consequently is not restricted to eicosanoids. Inhibition increases for polyunsaturated fatty acids comprising 18–22 carbons when cis-double bonds are close to the carboxyl group. Therefore the major natural (food-supplied) and mammalian endogenous fatty acids including -linolenic acid, mead acid, and arachidonic acid as well as the fully polyunsaturated 3-fatty acids that are enriched in fish oil eicosapentaenoic and docosahexaenoic acids are potent inhibitors of T-currents, which possibly contribute to their physiological functions.

Received for publication, October 26, 2006 , and in revised form, November 20, 2006.

^* This work was supported by the CNRS. 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. E-mail: jean.chemin{at}igf.cnrs.fr.

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