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Ligand‐induced down‐regulation of the cannabinoid 1 receptor is mediated by the G‐protein‐coupled receptor‐associated sorting protein GASP1
Author(s) -
Martini Lene,
Waldhoer Maria,
Pusch Margareta,
Kharazia Viktor,
Fong Jamie,
Lee Josephine H.,
Freissmuth Clarissa,
Whistler Jennifer L.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7132com
Subject(s) - cannabinoid receptor , gpr18 , receptor , g protein coupled receptor , cannabinoid , internalization , microbiology and biotechnology , 5 ht5a receptor , enzyme linked receptor , hek 293 cells , cannabinoid receptor type 2 , biology , chemistry , signal transduction , biochemistry , agonist
The cannabinoid 1 receptor (CB1R) is one of the most abundant seven transmembrane (7TM) spanning/G‐protein‐coupled receptors in the central nervous system and plays an important role in pain transmission, feeding, and the rewarding effects of cannabis. Tolerance to cannabinoids has been widely observed after long‐term use, with concomitant receptor desensitization and/or down‐regulation depending on the brain region studied. Several CB1R agonists promote receptor internalization after activation, but the postendocytic sorting of the receptor has not been studied in detail. Utilizing human embryonic kidney (HEK293) cells stably expressing the CB1R and primary cultured neurons expressing endogenous CB1R, we show that treatment with cannabinoid agonists results in CB1R degradation after endocytosis and that the G‐protein‐coupled receptor‐associated sorting protein GASP1 plays a major role in the postendocytic sorting process. Thus, these results may identify a molecular mechanism underlying tolerance and receptor down‐regulation after long‐term use of cannabinoids.—Martini, L., Waldhoer, M., Pusch, M., Kharazia, V., Fong, J., Lee, J. H., Freissmuth, C., Whistler, J. L. Ligand‐induced down‐regulation of the cannabinoid 1 receptor is mediated by the G‐protein‐coupled receptor‐associated sorting protein GASP1. FASEB J. 21, 802–811 (2007)