Jenkins L, et al. (2010) Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of beta-arrestin-2 and activate Galpha13. Biochem J 432(3):451-9
Abstract: The poorly characterised G protein-coupled receptor GPR35 has been suggested as a potential exploratory target for the treatment of both metabolic disorders and hypertension. It has also been indicated to play an important role in immune modulation. A major impediment to validation of these concepts and further study of the role of this receptor has been a paucity of pharmacological tools that interact with GPR35. Using a receptor-beta-arrestin 2 interaction assay with both human and rat orthologues of GPR35 we identified a number of compounds possessing agonist activity. These included the previously described ligand zaprinast. Although a number of active compounds, including cromolyn disodium and dicumarol, displayed similar potency at both orthologues of GPR35, a number of ligands, including pamoate and niflumic acid, had detectable activity only at human GPR35 whilst others, including zaprinast and luteolin, were markedly selective for the rat orthologue. Previous studies have demonstrated activation of Galpha13 by GPR35. A Saccharomyces cerevisiae-based assay employing a chimeric Gpa1-Galpha13 G protein confirmed that all of the compounds active at human GPR35 in the beta-arrestin-2 interaction assay were also able to promote cell growth via Galpha13. Each of these ligands also promoted binding of [35S]GTPgS to an epitope-tagged form of Galpha13 in a GPR35-dependent manner. The ligands identified in these studies will be useful in interrogating the biological actions of GPR35 but appreciation of the species selectivity of ligands at this receptor will be vital to correctly attribute function.
|Status: Published||Type: Journal Article||PubMed ID: 20919992|
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