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The Journal of Neuroscience, October 21, 2009, 29(42):13106-13114; doi:10.1523/JNEUROSCI.2919-09.2009

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Cellular/Molecular
T-Type Calcium Channel Inhibition Underlies the Analgesic Effects of the Endogenous Lipoamino Acids

Guillaume Barbara,¹ Abdelkrim Alloui,^2,3 Joël Nargeot,¹ Philippe Lory,¹ Alain Eschalier,^2,3 Emmanuel Bourinet,¹ and Jean Chemin¹

¹Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 5203, INSERM U661, Universités de Montpellier, 34094 Montpellier, France, and ²INSERM, UMR 766, and ³Clermont Université, Laboratoire de Pharmacologie Médicale, Faculté de Médecine, F-63000 Clermont-Ferrand, France

Correspondence should be addressed to Jean Chemin, Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, INSERM U661, Universités de Montpellier, 34094 Montpellier, France. Email: jean.chemin{at}igf.cnrs.fr

Lipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC₅₀ 200 nM for N-arachidonoyl 3-OH--aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3.2 steady-state inactivation and persisted during fatty acid amide hydrolase (FAAH) inhibition as well as in cell-free outside-out patch. In contrast, lipoamino acids had weak effects on high-voltage-activated (HVA) Cav1.2 and Cav2.2 calcium currents, on Nav1.7 and Nav1.8 sodium currents, and on anandamide-sensitive TRPV1 and TASK1 currents. Accordingly, lipoamino acids strongly inhibited native Cav3.2 currents in sensory neurons with small effects on sodium and HVA calcium currents. In addition, we demonstrate here that lipoamino acids NAGly and NAGABA-OH produced a strong thermal analgesia and that these effects (but not those of morphine) were abolished in Cav3.2 knock-out mice. Collectively, our data revealed lipoamino acids as a family of endogenous T-type channel inhibitors, suggesting that these ligands can modulate multiple cell functions via this newly evidenced regulation.

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Received June 19, 2009; accepted June 27, 2009.

Correspondence should be addressed to Jean Chemin, Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, INSERM U661, Universités de Montpellier, 34094 Montpellier, France. Email: jean.chemin{at}igf.cnrs.fr

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