Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1

Lene Martini, Maria Waldhoer, Margareta Pusch, Viktor Kharazia, Jamie Fong, Josephine H. Lee, Clarissa Freissmuth, Jennifer Whistler

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)802-811
Number of pages10
JournalFASEB Journal
Volume21
Issue number3
DOIs
StatePublished - Mar 1 2007
Externally publishedYes

Keywords

  • Degradation
  • GPCR
  • Postendocytic sorting
  • Tolerance

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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