Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 171, Issue 16, Pages 3908-3917Publisher
WILEY
DOI: 10.1111/bph.12746
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Funding
- National Institutes of Health National Institute on Drug Abuse [R01DA023204, T32DA007237, P30DA013429]
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Background and PurposeGPR18 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 (NAGly) and cannabinoids via differential G-protein coupled pathways, in addition to -arrestin signalling. Cellular localization of GPR18 receptors was also examined. Experimental ApproachCalcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addition, using the DiscoveRx PathHunter (R) CHO-K1 GPR18 -arrestin cell line, recruitment of -arrestin was quantified. Key ResultsConcentration-dependent increases in intracellular calcium and ERK1/2 phosphorylation were observed in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and (9)-tetrahydrocannabinol ((9)-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either G(q) or G(i/o) inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of -arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only (9)-THC produced a concentration-dependent response. The localization of GPR18 receptors within the HEK293/GPR18 cells is both intracellular, and on the plasma membrane. Conclusions and ImplicationsThese findings suggest that GPR18 activation involves several signal transduction pathways indicative of biased agonism, thereby providing a plausible explanation for the apparent discrepancies in GPR18 activation found in the literature. Additionally, the results presented herein provide further evidence for GPR18 as a candidate cannabinoid receptor.
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