G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease

Abstract

G protein-coupled receptor 35 (GPR35) is an orphan receptor, discovered in 1998, that has garnered interest as a potential therapeutic target through its association with a range of diseases. However, a lack of pharmacological tools and the absence of convincingly defined endogenous ligands have hampered the understanding of function necessary to exploit it therapeutically. Although several endogenous molecules can activate GPR35 none has yet been confirmed as the key endogenous ligand due to reasons that include lack of biological specificity, non-physiologically relevant potency and species ortholog selectivity. Recent advances have identified several highly potent synthetic agonists and antagonists, as well as agonists with equivalent potency at rodent and human orthologs, which will be useful as tool compounds. Homology modeling and mutagenesis studies have provided insight into the mode of ligand binding and possible reasons for the species selectivity of some ligands. Advances have also been made in determining the role of the receptor in disease. In the past, genome-wide association studies have associated GPR35 with diseases such as inflammatory bowel disease, type 2 diabetes, and coronary artery disease. More recent functional studies have implicated it in processes as diverse as heart failure and hypoxia, inflammation, pain transduction and synaptic transmission. In this review, we summarize the progress made in understanding the molecular pharmacology, downstream signaling and physiological function of GPR35, and discuss its emerging potential applications as a therapeutic target.

Disruption of GPR35 Exacerbates Dextran Sulfate Sodium-Induced Colitis in Mice

“…G protein-coupled receptor 35 (GPR35) is an “orphan” receptor identified in 1998 [8] and has gained significant attention as a vital therapeutic task largely due to its close pathophysiological association with a plethora of diseases [9]. Nonetheless, the limitation in pharmacological approach and the lack of known endogenous ligands have led to a poor understanding of the therapeutic potential targeting this receptor.…”

Elevated kynurenine pathway metabolism during neurodevelopment: Implications for brain and behavior

“…KYNA, whose mammalian brain concentrations in adulthood are in the nanomolar to low micromolar range, exerts neuroactive properties as an antagonist of the alpha 7 nicotinic acetylcholine (α7nACh) receptors (Hilmas et al, 2001) and N-methyl-D-aspartate (NMDA) receptors (Perkins and Stone, 1982). KYNA also acts as a ligand of G protein-coupled receptor (GPR) 35 and the aryl hydrocarbon receptor (AhR), two signaling receptors that are functional in both the brain and peripheral organs (Divorty et al, 2015; Julliard et al, 2014; Mackenzie and Milligan, 2015; Moroni et al, 2012; Noakes, 2015). The second branch of the KP is predominantly metabolized in microglial cells (Guillemin et al, 2001, 2003; Heyes et al, 1996; Saito and Heyes, 1996), where the enzyme kynurenine 3-monooxygenase (KMO) metabolizes kynurenine to 3-hydroxykynurenine (3-HK), and the downstream catabolite 3-hydroxyanthranilic acid is formed by the enzyme kynureninase.…”

GPR35 mediates lodoxamide‐induced migration inhibitory response but not CXCL17‐induced migration stimulatory response in THP‐1 cells; is GPR35 a receptor for CXCL17?

“…For a considerable time, GPR35 was considered an orphan receptor as no endogenous ligand had been discovered. Several endogenous molecules, such as lysophosphatidic acid, kynurenic acid , cGMP and reverse T3, were proposed as ligands (Wang et al, ; Oka et al, ; Jenkins et al, ; Deng et al, ; Southern et al, ), but their potencies were too low (in the μM range) to support their roles as GPR35 ligands (Divorty et al, ). Synthetic surrogate agonists, such as zaprinast , pamoic acid , compound 1, PSB‐13253 and lodoxamide, have been successfully identified or developed (Taniguchi et al, ; Jenkins et al, ; Zhao et al, ; Funke et al, ; Neetoo‐Isseljee et al, ; Thimm et al, ; MacKenzie et al, ), and of these lodoxamide most potently interacts with human and rodent GPR35 (MacKenzie et al, ).…”