Abstract
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 “off-target” 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.
Highlights
GPR35 is a class A, rhodopsin-like G protein-coupled receptor (GPCR) first identified more than 20 years ago
Pubs.acs.org/ptsci for example, as kynurenic acid and zaprinast reduced rather than mimicked the effect of CXCL17 in neuropathic pain in mice,[15] these results are not consistent with CXCL17 acting via GPR35
GPCR antisera, we recently generated a transgenic knock-in mouse line in which we introduced the hemeagglutinin (HA)
Summary
The human GPR35 gene can be transcribed and translated into three variants.[1]. Variants 2 and 3 both encode the same longer isoform, GPR35b, which differs from GPR35a by an additional N-terminal extension of 31 amino acids, resulting in a longer extracellular domain but subsequent equivalence in sequence (Figure 1). The extracellular domain of GPR35b does not appear to result in differential targeting as the isoforms localize to similar subcellular compartments when expressed in human HeLa cells and in rat neurons.[4] Sequence comparisons highlight the potential of GPR35b to form an additional extracellular disulfide interaction compared to GPR35a (Figure 1), but this, or its consequences, has yet to be examined directly. The pharmacology of GPR35 is generally quite distinct between human and rat GPR35 (Table 1), given that both lodoxamide and bufrolin are potent agonists at both these orthologues[5] and both are symmetric diacids (Table 1), researchers [9] and, more extensively,[5] explored the contribution of various positively charged residues in these orthologues to attempt to define the agonist binding pocket and whether variation in such residues might help explain species selectivity of other. As the more deeply located 4.62 is positively charged in this orthologue, it is possible that ligands sit further down in the pocket of the rat receptor. In the continuing absence of direct structural details, the insights from these studies were not definitive in defining the basis of species ligand selectivity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
