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Activation of GPR 18 by cannabinoid compounds: a tale of biased agonism
Author(s) -
ConsoleBram Linda,
Brailoiu Eugen,
Brailoiu Gabriela Cristina,
Sharir Haleli,
Abood Mary E
Publication year - 2014
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/bph.12746
Subject(s) - gpr18 , cannabinoid , cannabinoid receptor antagonist , microbiology and biotechnology , cannabinoid receptor , g protein coupled receptor , biology , anandamide , chemistry , biochemistry , signal transduction , receptor , agonist
Background and Purpose GPR 18 is a candidate cannabinoid receptor, but its classification as such is controversial. The rationale of the study presented herein was to consider the effects of N ‐arachidonoyl glycine ( NAG ly) and cannabinoids via differential G ‐protein coupled pathways, in addition to β‐arrestin signalling. Cellular localization of GPR 18 receptors was also examined. Experimental Approach Calcium mobilization and ERK 1/2 phosphorylation were quantified in a cell line stably expressing GPR 18 ( HEK 293/ GPR 18 cells). In addition, using the D iscove R x P ath H unter® CHO ‐ K 1 GPR 18 β‐arrestin cell line, recruitment of β‐arrestin was quantified. Key Results Concentration‐dependent increases in intracellular calcium and ERK 1/2 phosphorylation were observed in the presence of NAG ly, abnormal cannabidiol ( AbnCBD ), O ‐1602, O ‐1918 and Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐ THC ) in HEK 293/ GPR 18 cells. The initial rise in intracellular calcium in the presence of NAG ly, O 1918 and THC was blocked by either G α q or G α i/o inhibition. The ERK 1/2 phosphorylation was inhibited by Pertussis toxin and N ‐arachidonoyl‐ L ‐serine ( NARAS ). Recruitment of β‐arrestin in the PathHunter CHO ‐ K 1 GPR 18 cell line revealed a differential pattern of GPR 18 activation; of all the ligands tested, only Δ 9 ‐ THC produced a concentration‐dependent response. The localization of GPR 18 receptors within the HEK 293/ GPR 18 cells is both intracellular, and on the plasma membrane. Conclusions and Implications These findings suggest that GPR 18 activation involves several signal transduction pathways indicative of biased agonism, thereby providing a plausible explanation for the apparent discrepancies in GPR 18 activation found in the literature. Additionally, the results presented herein provide further evidence for GPR 18 as a candidate cannabinoid receptor.