Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13

Jenkins, L. , Brea, J., Smith, N.J., Hudson, B.D. , Reilly, G., Bryant, N.J., Castro, M., Loza, M.I. and Milligan, G. (2010) Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13. Biochemical Journal, 432(3), pp. 451-459. (doi: 10.1042/BJ20101287)

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Publisher's URL: http://dx.doi.org/10.1042/BJ20101287

Abstract

The poorly characterized 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 whereas others, including zaprinast and luteolin, were markedly selective for the rat orthologue. Previous studies have demonstrated activation of G(alpha 13) by GPR35. A Saccharomyces cerevisiae-based assay employing a chimaeric Gpal-G(alpha 13) 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 G(alpha 13). Each of these ligands also promoted binding of [S-35]GTP[S] (guanosine 5'-[gamma-[S-35]thio]triphosphate) to an epitope-tagged form of G,3 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jenkins, Mrs Laura and Hudson, Dr Brian and Milligan, Professor Graeme and Bryant, Dr Nia and Smith, Dr Nicola
Authors: Jenkins, L., Brea, J., Smith, N.J., Hudson, B.D., Reilly, G., Bryant, N.J., Castro, M., Loza, M.I., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:Biochemical Journal
ISSN:0264-6021

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