The GPCR-associated sorting protein 1 regulates ligand-induced down-regulation of GPR55

Julia Kargl, N. A. Balengal, W. Platzer, L. Martini, Jennifer Whistler, Maria Waldhoer

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


BACKGROUND AND PURPOSE: Many GPCRs, including the CB 1 cannabinoid receptor, are down-regulated following prolonged agonist exposure by interacting with the GPCR-associated sorting protein-1 (GASP-1). The CB 1 receptor antagonist rimonabant has also recently been described to be an agonist at GPR55, a cannabinoid-related receptor. Here we investigated the post-endocytic properties of GPR55 after agonist exposure and tested whether GASP-1 is involved in this process. EXPERIMENTAL APPROACH: We evaluated the direct protein-protein interaction of GPR55 with GASP-1 using (i) GST-binding assays and (ii) co-immunoprecipitation assays in GPR55-HEK293 cells with endogenous GASP-1 expression. We further tested the internalization, recycling and degradation of GPR55 using confocal fluorescence microscopy and biotinylation assays in the presence and absence of GASP-1 (lentiviral small hairpin RNA knockdown of GASP-1) under prolonged agonist [rimonabant (RIM), lysophosphatidylinositol (LPI)] stimulation. KEY RESULTS: We showed that the prolonged activation of GPR55 with rimonabant or LPI down-regulates GPR55 via GASP-1. GASP-1 binds to GPR55 in vitro, and this interaction was required for targeting GPR55 for degradation. Disrupting the GPR55-GASP-1 interaction prevented post-endocytic receptor degradation, and thereby allowed receptor recycling. CONCLUSION AND IMPLICATIONS: These data implicate GASP-1 as an important regulator of ligand-mediated down-regulation of GPR55. By identifying GASP-1 as a key regulator of the trafficking and, by extension, functional expression of GPR55, we may be one step closer to gaining a better understanding of this receptor in response to cannabinoid drugs. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit 2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit

Original languageEnglish (US)
Pages (from-to)2611-2619
Number of pages9
JournalBritish Journal of Pharmacology
Issue number8
StatePublished - Apr 1 2012
Externally publishedYes


  • Degradation
  • GASP-1
  • GPCR
  • GPR55
  • LPI
  • Rimonabant

ASJC Scopus subject areas

  • Pharmacology


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