Multiple tyrosine metabolites are GPR35 agonists

Abstract

Both kynurenic acid and 2-acyl lysophosphatidic acid have been postulated to be the endogenous agonists of GPR35. However, controversy remains whether alternative endogenous agonists exist. The molecular targets accounted for many nongenomic actions of thyroid hormones are mostly unknown. Here we report the agonist activity of multiple tyrosine metabolites at the GPR35. Tyrosine metabolism intermediates that contain carboxylic acid and/or catechol functional groups were first selected. Whole cell dynamic mass redistribution (DMR) assays enabled by label-free optical biosensor were then used to characterize their agonist activity in native HT-29. Molecular assays including β-arrestin translocation, ERK phosphorylation and receptor internalization confirmed that GPR35 functions as a receptor for 5,6-dihydroxyindole-2-carboxylic acid, 3,3′,5′-triiodothyronine, 3,3′,5-triiodothyronine, gentisate, rosmarinate, and 3-nitrotyrosine. These results suggest that multiple tyrosine metabolites are alternative endogenous ligands of GPR35, and GPR35 may represent a druggable target for treating certain diseases associated with abnormality of tyrosine metabolism.

Label-free cell phenotypic profiling decodes the composition and signaling of an endogenous ATP-sensitive potassium channel

“…2i). These results suggest that similar to several other GPR35 agonists including benserazide37, tolcapone38 and rosmarinic acid39, flufenamic acid not only activates the endogenous GPR35 in HT29, but also activates an additional unknown receptor. Of note, we did not determine the mechanism accounted for the DMR of IAA-94 in HT29, given that the IAA-94 DMR is much smaller than those induced by GPR35 agonists.…”

Endurance exercise increases skeletal muscle kynurenine aminotransferases and plasma kynurenic acid in humans

“…Indeed, specific agonists confirmed that GPR35-downstream signaling modulates glucose homeostasis in metabolic tissues (188). In addition, GPR35 appears to be activated by several endogenous ligands and to be mainly coupled to G-alpha subunits (Figure 14) (76,210). It was also shown that, in addition to GPR35-mediated regulation of inflammatory processes (95,339), this receptor is activated endogenously by chemokine (C-X-C-motif) ligand 17 (CXCL17) at nM concentrations (215).…”

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, ).…”