Therapeutic Opportunities and Challenges in Targeting the Orphan G Protein-Coupled Receptor GPR35

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, 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 the following: (i) 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. (ii) Humans express two distinct protein isoform sequences, while rodents express only a single form. (iii) The pharmacologies of the human and rodent orthologues of GPR35 are very distinct, with variation between rat and mouse GPR35 being as marked as that between either of these species and the human forms. 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 a 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 offtarget effects of presumptive GPR35 ligands can be better defined, as well as a clear understanding of the human isoform expression profile and its significance at both tissue and individual cell levels.