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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: fj.07-102731v1 fj.07-102731v2 22/7/2311    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Rozenfeld, R. Articles by Devi, L. A. Search for Related Content PubMed PubMed Citation Articles by Rozenfeld, R. Articles by Devi, L. A.

Regulation of CB₁ cannabinoid receptor trafficking by the adaptor protein AP-3

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, USA

¹Correspondence: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, 19–84 Annenberg Bldg., One Gustave L. Levy Place, New York, NY 10029, USA. E-mail: lakshmi.devi{at}mssm.edu

Cannabinoid receptor 1 (CB₁) is an abundant G protein-coupled receptor, involved in a number of physiological processes. This receptor is localized at the plasma membrane, as well as in intracellular vesicles. The trafficking events leading to this intracellular localization remain controversial. In this study, we examine the differential trafficking of CB₁ receptors and its implication on signaling. We find that the transfected tagged receptors are predominantly at the plasma membrane, whereas endogenous receptors exhibit an intracellular localization. We also find that intracellular endogenous CB₁ receptors do not have an endocytic origin. Instead, these receptors associate with the adaptor protein AP-3 and traffic to the lysosomes. siRNA-mediated AP-3 knockdown leads to enhanced cell surface localization of CB₁ receptors. Finally, we show that CB₁ receptors in the late endosomal/lysosomal compartment are associated with heterotrimeric G proteins and mediate signal transduction. These results suggest that intracellular CB₁ receptors are functional and that their spatial segregation is likely to significantly affect receptor function.—Rozenfeld, R., Devi, L. A. Regulation of CB₁ cannabinoid receptor trafficking by the adaptor protein AP-3.

Key Words: endocannabinoid • G protein-coupled receptors • intracellular signaling • lysosomal sorting • addiction • drug of abuse • THC