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J. Biol. Chem., Vol. 282, Issue 11, 7753-7757, March 16, 2007

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The Role of Diacylglycerol Lipase in Constitutive and Angiotensin AT₁ Receptor-stimulated Cannabinoid CB1 Receptor Activity^*

Gábor Turu, Anne Simon^¶, Pál Gyombolai, László Szidonya, György Bagdy^||**, Zsolt Lenkei^¶, and László Hunyady¹

From the Department of Physiology, Semmelweis University, Faculty of Medicine, H-1444 Budapest, Hungary, the Laboratory of Neurobiochemistry and Molecular Physiology, Hungarian Academy of Sciences and Semmelweis University, H-1444 Budapest, Hungary, the ^¶Laboratoire Neurobiologie et Diversité Cellulaire, Ecole Supérieure de Physique et de Chimie Industrielles-Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7637, 75013 Paris, France, the ^**Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, H-1021 Budapest, Hungary, and the ^||Group of Neuropsychopharmacology, Hungarian Academy of Sciences and Semmelweis University, H-1089 Budapest, Hungary

The cannabinoid CB1 receptor (CB1R) is a G protein-coupled receptor, which couples to the G_i/o family of heterotrimeric G proteins. The receptor displays both basal and agonist-induced signaling and internalization. Although basal activity of CB1Rs is attributed to constitutive (agonist-independent) receptor activity, studies in neurons suggested a role of postsynaptic endocannabinoid (eCB) release in the persistent activity of presynaptic CB1Rs. To elucidate the role of eCBs in basal CB1R activity, we have investigated the role of diacylglycerol lipase (DAGL) in this process in Chinese hamster ovary (CHO) cells, which are not targeted specifically with eCBs. Agonist-induced G protein activation was determined by detecting dissociation G protein subunits expressed in CHO cells with bioluminescence resonance energy transfer (BRET), after labeling the and subunits with Renilla luciferase and enhanced yellow fluorescent protein (EYFP), respectively. Preincubation of the cells with tetrahydrolipstatin (THL), a known inhibitor of DAGLs, caused inhibition of the basal activity of CB1R. Moreover, preincubation of CHO and cultured hippocampal neurons with THL increased the number of CB1Rs on the cell membrane, which reflects its inhibitory action on CB1R internalization in non-simulated cells. In CHO cells co-expressing CB1R and angiotensin AT₁ receptors, angiotensin II-induced G_o protein activation that was blocked by both a CB1R antagonist and THL. These data indicate that cell-derived eCB mediators have a general role in the basal activity of CB1Rs in non-neural cells and neurons, and that this mechanism can be stimulated by AT₁ receptor activation.

Received for publication, December 26, 2006 , and in revised form, January 11, 2007.

^* This work was supported in part by grants from the Hungarian Science Foundation (OTKA T-046445, M-045341, and Ts-049851), theÁ_nyos Jedlik program (NKFP1–010/2005), the Hungarian Ministry of Public Health (ETT 447/2006 and 460/2006), and the European Community (LSHM-CT-2004–503474). 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: Dept. of Physiology, Semmelweis University, H-1444 Budapest, P. O. Box 259, Hungary. Tel.: 36-1-266-9180; Fax: 36-1-266-6504; E-mail: Hunyady{at}puskin.sote.hu.

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