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

92 Citations (Scopus)

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

Fingerprint

Cannabinoid Receptors
Cannabinoids
Protein Transport
G-Protein-Coupled Receptors
Sorting
Down-Regulation
Cannabinoid Receptor Agonists
Ligands
Proteins
HEK293 Cells
Cannabis
Endocytosis
Central Nervous System
Kidney
Neurons
Pain
Neurology
Brain
Chemical activation
Degradation

Keywords

  • Degradation
  • GPCR
  • Postendocytic sorting
  • Tolerance

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. / Martini, Lene; Waldhoer, Maria; Pusch, Margareta; Kharazia, Viktor; Fong, Jamie; Lee, Josephine H.; Freissmuth, Clarissa; Whistler, Jennifer.

In: FASEB Journal, Vol. 21, No. 3, 01.03.2007, p. 802-811.

Research output: Contribution to journalArticle

Martini, Lene ; Waldhoer, Maria ; Pusch, Margareta ; Kharazia, Viktor ; Fong, Jamie ; Lee, Josephine H. ; Freissmuth, Clarissa ; Whistler, Jennifer. / Ligand-induced down-regulation of the cannabinoid 1 receptor is mediated by the G-protein-coupled receptor-associated sorting protein GASP1. In: FASEB Journal. 2007 ; Vol. 21, No. 3. pp. 802-811.
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