Therapeutic opportunities and challenges in targeting the orphan G protein-coupled receptor GPR35

Quon, T., Lin, L.-C., Ganguly, A., Tobin, A. B. and Milligan, G. (2020) Therapeutic opportunities and challenges in targeting the orphan G protein-coupled receptor GPR35. ACS Pharmacology and Translational Science, 3(5), pp. 801-812. (doi: 10.1021/acsptsci.0c00079) (PMID:33073184)

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GPR35 is a class A, rhodopsin-like G protein-coupled receptor (GPCR) first identified more than 20 years ago. In the intervening period identification of strong expression in the lower intestine and colon, as well as in a variety of immune cells including monocytes and a variety of dendritic cells, and in dorsal root ganglia, has suggested potential therapeutic opportunities in targeting this receptor in a range of conditions. GPR35 is, however, unusual in a variety of ways that challenge routes to translation. These include that although a substantial range and diversity of endogenous ligands have been suggested as agonist partners for this receptor it officially remains defined as an ‘orphan’ GPCR; that humans express two distinct protein isoform sequences whilst rodents express only a single form, and that the pharmacology of the human and rodent orthologues of GPR35 is very distinct, with variation between rat and mouse GPR35 as marked as between either of these species and the human forms. 2 Herein we provide perspectives on each of the topics above as well as suggesting ways to overcome the challenges currently hindering potential translation. These include better understanding of the extent and molecular basis for species selective GPR35 pharmacology and the production of novel mouse models in which both ‘on-target’ and ‘off-target’ effects of presumptive GPR35 ligands can be better defined as well as clear understanding in human of isoform expression profile and its significance at both tissue and individual cell level.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Quon, Dr Tezz and Ganguly, Amlan and Milligan, Professor Graeme and Tobin, Andrew and Lin, Dr Li-Chiung
Authors: Quon, T., Lin, L.-C., Ganguly, A., Tobin, A. B., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:ACS Pharmacology and Translational Science
Publisher:American Chemical Society
ISSN (Online):2575-9108
Published Online:29 July 2020
Copyright Holders:Copyright © 2020 American Chemical Society
First Published:First published in ACS Pharmacology and Translational Science 3(5):801-812
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
173305Defining the functional roles of the enigmatic G protein coupled receptor GPR35Graeme MilliganBiotechnology and Biological Sciences Research Council (BBSRC)BB/P000649/1MCSB - Molecular Pharmacology
173689Defining the functional role of the enigmatic G protein coupled receptor GPR35 - Leicester application - PART BAndrew TobinBiotechnology and Biological Sciences Research Council (BBSRC)BB/P00069X/1MCSB - Administration