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Br J Pharmacol. 2010 Jun;160(3):604-14. doi: 10.1111/j.1476-5381.2009.00625.x. Epub 2010 Feb 5.

GPR55 ligands promote receptor coupling to multiple signalling pathways.

Author information

1
Division of Medical Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.

Abstract

BACKGROUND AND PURPOSE:

Although GPR55 is potently activated by the endogenous lysophospholipid, L-alpha-lysophosphatidylinositol (LPI), it is also thought to be sensitive to a number of cannabinoid ligands, including the prototypic CB1 receptor antagonists AM251 and SR141716A (Rimonabant). In this study we have used a range of functional assays to compare the pharmacological activity of selected cannabinoid ligands, AM251, AM281 and SR141716A with LPI in a HEK293 cell line engineered to stably express recombinant, human GPR55.

EXPERIMENTAL APPROACH:

We evaluated Ca(2+) signalling, stimulation of extracellular signal regulated kinase (ERK1/2) mitogen activated kinase MAP-kinases, induction of transcriptional regulators that are downstream of GPR55, including nuclear factor of activated T cells (NFAT), nuclear factor-kappaB (NF-kappaB) and cAMP response element binding protein (CREB), as well as receptor endocytosis. In addition, we assessed the suitability of a novel, label-free assay for GPR55 ligands that involves optical measurement of dynamic mass redistribution following receptor activation.

KEY RESULTS:

GPR55 linked to a range of downstream signalling events and that the activity of GPR55 ligands was influenced by the functional assay employed, with differences in potency and efficacy observed.

CONCLUSIONS AND IMPLICATIONS:

Our data help to resolve some of the issues surrounding the pharmacology of cannabinoid ligands at GPR55 and highlight some differences in effector coupling associated with distinct GPR55 ligands.

PMID:
20136841
PMCID:
PMC2931561
DOI:
10.1111/j.1476-5381.2009.00625.x
[Indexed for MEDLINE]
Free PMC Article

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