GPR35: from enigma to therapeutic target

G protein–receptor kinases 5/6 are the key regulators of G protein–coupled receptor 35–arrestin interactions

“…8 A ). We selected zaprinast for these studies both because this was the ligand used by ( 5 ) for earlier studies on the mouse orthologue and because lodoxamide has only modest potency at mouse GPR35 ( 12 ). Pretreatment with compound 19 prior to addition of zaprinast fully eliminated agonist-induced recognition of mouse GPR35-HA by the anti-pSer 298 -pSer 301 antiserum ( Fig.…”

“…Herein, we built on previous work in which we defined the sites of agonist-regulated phosphorylation in GPR35 ( 5 ). This receptor can be activated by the endogenously produced tryptophan metabolite kynurenic acid and by a considerable number of synthetic ligands ( 12 ) but is still officially designated as an orphan GPCR ( 11 ). Despite this, significant expression in crypts of the colon and a clear association between a single nucleotide polymorphism that results in a T108M variation in transmembrane III of the protein and inflammatory diseases of the lower gut ( 11 ) has promoted substantial interest in the concept that agonists of GPR35 might be effective in the treatment of ulcerative colitis and related disorders ( 12 ).…”

“…One area in which this knowledge is generally lacking is for receptors which have, until now, been understudied but for which there is an emerging interest in their potential as novel targets for the treatment of human disease. One such receptor is GPR35, which is currently attracting considerable interest as a therapeutic target in areas ranging from lower gut inflammation to nonalcoholic steatohepatitis ( 11 , 12 ). The sites of agonist-induced phosphorylation in GPR35 cluster within the relatively short, intracellular C-terminal tail and have been mapped by combinations of mass spectrometry, [ 32 P] labeling and mutagenesis ( 5 ).…”

GPR35 acts a dual role and therapeutic target in inflammation

“…Despite various endogenous ligands of GPR35, a definitive endogenous activator has not yet been firmly established, which maintains its status as an orphan receptor ( 13 ). Human GPR35 gene is transcribed and translated into three distinct variants ( 16 ).…”

“…It interacts with several signaling pathways, such as MAPK, NF-κB and others, thereby modulating inflammatory signaling dynamics. Furthermore, the functionality of GPR35 can be influenced by various ligands, ranging from endogenous metabolites to synthetic compounds, thus impacting its downstream effects in the inflammation process ( 13 ). Through these complex interactions and functions, GPR35 illustrates the multifactorial nature of inflammation and the intricate molecular dance that enables the body to respond appropriately to internal and external stressors.…”