Tags

Type your tag names separated by a space and hit enter

Activation of GPR18 by cannabinoid compounds: a tale of biased agonism.
Br J Pharmacol. 2014 Aug; 171(16):3908-17.BJ

Abstract

BACKGROUND AND PURPOSE

GPR18 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 β-arrestin signalling. Cellular localization of GPR18 receptors was also examined.

EXPERIMENTAL APPROACH

Calcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addition, using the DiscoveRx PathHunter CHO-K1 GPR18 β-arrestin cell line, recruitment of β-arrestin was quantified.

KEY RESULTS

Concentration-dependent increases in intracellular calcium and ERK1/2 phosphorylation were observed in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either Gα(q) or Gα(i/o) inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of β-arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only Δ(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 IMPLICATIONS

These 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.

Links

PMC Free PDF

Authors+Show Affiliations

Console-Bram L
Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
Brailoiu E
No affiliation info available
Brailoiu GC
No affiliation info available
Sharir H
No affiliation info available
Abood ME
No affiliation info available

MeSH

AnimalsArachidonic AcidsArrestinsCHO CellsCalciumCannabidiolCannabinoid Receptor AgonistsCricetulusCyclohexanesDronabinolGlycineHEK293 CellsHumansMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Receptors, G-Protein-CoupledResorcinolsSignal Transductionbeta-Arrestins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24762058

Citation

Console-Bram, Linda, et al. "Activation of GPR18 By Cannabinoid Compounds: a Tale of Biased Agonism." British Journal of Pharmacology, vol. 171, no. 16, 2014, pp. 3908-17.
Console-Bram L, Brailoiu E, Brailoiu GC, et al. Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. Br J Pharmacol. 2014;171(16):3908-17.
Console-Bram, L., Brailoiu, E., Brailoiu, G. C., Sharir, H., & Abood, M. E. (2014). Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. British Journal of Pharmacology, 171(16), 3908-17. https://doi.org/10.1111/bph.12746
Console-Bram L, et al. Activation of GPR18 By Cannabinoid Compounds: a Tale of Biased Agonism. Br J Pharmacol. 2014;171(16):3908-17. PubMed PMID: 24762058.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. AU - Console-Bram,Linda, AU - Brailoiu,Eugen, AU - Brailoiu,Gabriela Cristina, AU - Sharir,Haleli, AU - Abood,Mary E, PY - 2013/11/08/received PY - 2014/04/03/revised PY - 2014/04/18/accepted PY - 2014/4/26/entrez PY - 2014/4/26/pubmed PY - 2015/4/10/medline SP - 3908 EP - 17 JF - British journal of pharmacology JO - Br J Pharmacol VL - 171 IS - 16 N2 - BACKGROUND AND PURPOSE: GPR18 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 β-arrestin signalling. Cellular localization of GPR18 receptors was also examined. EXPERIMENTAL APPROACH: Calcium mobilization and ERK1/2 phosphorylation were quantified in a cell line stably expressing GPR18 (HEK293/GPR18 cells). In addition, using the DiscoveRx PathHunter CHO-K1 GPR18 β-arrestin cell line, recruitment of β-arrestin was quantified. KEY RESULTS: Concentration-dependent increases in intracellular calcium and ERK1/2 phosphorylation were observed in the presence of NAGly, abnormal cannabidiol (AbnCBD), O-1602, O-1918 and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) in HEK293/GPR18 cells. The initial rise in intracellular calcium in the presence of NAGly, O1918 and THC was blocked by either Gα(q) or Gα(i/o) inhibition. The ERK1/2 phosphorylation was inhibited by Pertussis toxin and N-arachidonoyl-L-serine (NARAS). Recruitment of β-arrestin in the PathHunter CHO-K1 GPR18 cell line revealed a differential pattern of GPR18 activation; of all the ligands tested, only Δ(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 IMPLICATIONS: These 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. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/24762058/Activation_of_GPR18_by_cannabinoid_compounds:_a_tale_of_biased_agonism_ DB - PRIME DP - Unbound Medicine ER -