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GPR55 ligands promote receptor coupling to multiple signalling pathways
Author(s) -
Henstridge Christopher M,
Balenga Nariman AB,
Schröder Ralf,
Kargl Julia K,
Platzer Wolfgang,
Martini Lene,
Arthur Simon,
Penman June,
Whistler Jennifer L,
Kostenis Evi,
Waldhoer Maria,
Irving Andrew J
Publication year - 2010
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00625.x
Subject(s) - am251 , cannabinoid receptor , cannabinoid , microbiology and biotechnology , rimonabant , cannabinoid receptor type 2 , cannabinoid receptor antagonist , receptor , nfat , kinase , chemistry , mapk/erk pathway , endocannabinoid system , signal transduction , biology , transcription factor , pharmacology , biochemistry , agonist , gene
Background and purpose: Although GPR55 is potently activated by the endogenous lysophospholipid, L‐α‐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‐κB (NF‐κB) 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.