{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n G protein‐coupled receptor 35 (GPR35) has emerged as a multifunctional receptor that integrates diverse extracellular signals to regulate metabolic, immune, cardiovascular, and neural functions. Endogenous ligands including kynurenic acid have been shown to activate GPR35 in adipose tissue, thereby stimulating lipid metabolism, thermogenic and anti‐inflammatory gene expression that improves energy utilization and glucose tolerance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Genetic studies have further implicated GPR35 in gastrointestinal inflammatory disorders: specific missense variants are associated with increased susceptibility to primary sclerosing cholangitis and inflammatory bowel disease (IBD) including ulcerative colitis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, GPR35 has been identified as the receptor for the mucosal chemokine CXCL17, suggesting a chemotactic role in mucosal innate immunity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": ", while 2‐acyl lysophosphatidic acid, another endogenous mediator, signals via GPR35 to trigger sustained Ca²⁺ mobilization and ERK1/2 phosphorylation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In invariant natural killer T cells, receptor activation attenuates the release of interleukin‐4 via Gi/o–protein–dependent mechanisms"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", and additional pharmacological studies have characterized species‐selective agonists and coupling to Gα13."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the cardiovascular system, hypoxia‐induced upregulation of GPR35 in cardiomyocytes appears to mediate cytoskeletal alterations and may serve as an early marker of cardiac stress and failure"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", while receptor deficiency or pharmacological modulation alters blood pressure responses and vascular remodeling through effects on smooth muscle and endothelial cell migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n GPR35 also contributes to innate immune cell recruitment; activated neutrophils upregulate GPR35 and respond to platelet‐derived 5‐hydroxyindoleacetic acid to facilitate transmigration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In the nervous system, receptor expression in rat sympathetic neurons tonically inhibits N‐type Ca²⁺ channels and modulates synaptic transmission"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", and in cultured astrocytes, GPR35 activation modulates cAMP production and the plateau phase of intracellular Ca²⁺ fluxes, potentially contributing to decreases in extracellular glutamate levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In disease contexts, loss or altered signaling of GPR35 affects tissue homeostasis; for example, its deficiency is linked to worsened experimental colitis, impaired epithelial goblet cell function, and dysbiosis in the intestine"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while in tumors, increased GPR35 expression correlates with higher proliferation and migration in breast and colon cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Finally, selective agonists such as zaprinast and pamoic acid have demonstrated antinociceptive and neuroprotective properties in rodent models of stroke, highlighting the therapeutic potential of targeting GPR35 in pain and cardiovascular pathologies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings indicate that GPR35 functions as a critical metabolic and immunomodulatory receptor whose diverse ligand interactions influence energy homeostasis, inflammatory responses, cardiovascular dynamics, neuronal excitability, and tumorigenesis, thereby representing a promising target for therapeutic intervention (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18).\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Leandro Z Agudelo, Duarte M S Ferreira, Igor Cervenka, et al. 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