Review
CB1 cannabinoid receptor-G protein association: a possible mechanism for differential signaling

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Abstract

Effects of cannabinoid compounds on neurons are predominantly mediated by the CB1 cannabinoid receptor. Onset of signaling cascades in response to cannabimimetic drugs is triggered by the interaction of the cannabinoid receptor with Gi/o proteins. Much work has been done to delineate the cannabinoid agonist-induced downstream signaling events; however, it remains to define the molecular basis of cannabinoid receptor-G protein interactions that stimulate these signaling pathways. In this review, we discuss several signal transduction pathways, focusing on studies that demonstrate the efficacy of CB1 receptor agonists through G protein mediated pathways.

Section snippets

CB1 cannabinoid receptor mediated signal transduction

The CB1 cannabinoid receptor is a G protein coupled receptor (GPCR), comprising seven transmembrane (TM) helices (Fig. 1). Agonist ligands (classical (Δ9-tetrahydrocannabinol (THC), HU210) and non-classical (CP55940, CP55244) cannabinoids, aminoalkylindoles (WIN55212-2) and eicosanoids (anandamide, 2-arachidonoylglycerol)) interact with the receptor within the pore formed within the TM helical cluster. The three cytosolic loops and a putative fourth loop formed by palmitoylation at the

Mechanism by which the CB1 receptor interacts with G proteins to mediate signal transduction

Although the role of the CB1 receptor and Gi/o proteins in the activation of different signal transduction pathways has been well established, the molecular mechanism by which the CB1 receptor activates specific Gi/o proteins as well as the regulation of this interaction was not clearly understood. Recent studies from our laboratory have shed light on the interaction of CB1 receptors with specific Gi/o protein subtypes in neuronal cells.

Prospectus

It should be noted that throughout these detergent solubilization and coimmunoprecipitation studies, the CB1 receptor-Gα complexes exist in the absence of exogenously added agonist ligands. This phenomenon differs from what has been observed for many GPCR-G protein interactions in which addition of agonists (in the absence of GTP) was required. We have speculated that this facile association may contribute to the constitutively active behavior attributed to the cannabinoid receptors which has

Acknowledgements

This work was supported by National Institute on Drug Abuse grants U24-DA12385, R01-DA03690, R01-DA06312, K05-DA00182 to ACH; F06-NS11111 to A-AA; and AHA Beginning Grant in Aid 0060377Z to SM. We thank Skyla Carney for assistance with the NO experiments.

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    Address: Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of South Carolina, Columbia, SC 29208, USA.

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