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GPR35

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Target id: 102

Nomenclature: GPR35

Family: Class A Orphans

This receptor has a proposed ligand; see the Latest Pairings page for more information.

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 309 2q37.3 GPR35 G protein-coupled receptor 35
Mouse 7 307 1 D Gpr35 G protein-coupled receptor 35
Rat 6 306 9q36 Gpr35 G protein-coupled receptor 35
Previous and Unofficial Names Click here for help
G-protein coupled receptor 3 | KYNA receptor | Kynurenic acid receptor
Database Links Click here for help
Specialist databases
GPCRdb gpr35_human (Hs), gpr35_mouse (Mm), q33bm1_rat (Rn)
Other databases
Alphafold Q9HC97 (Hs), Q9ES90 (Mm), Q33BM1 (Rn)
ChEMBL Target CHEMBL1293267 (Hs), CHEMBL2390813 (Mm), CHEMBL2390812 (Rn)
Ensembl Gene ENSG00000178623 (Hs), ENSMUSG00000026271 (Mm), ENSRNOG00000062887 (Rn)
Entrez Gene 2859 (Hs), 64095 (Mm), 367315 (Rn)
Human Protein Atlas ENSG00000178623 (Hs)
KEGG Gene hsa:2859 (Hs), mmu:64095 (Mm), rno:367315 (Rn)
OMIM 602646 (Hs)
Orphanet ORPHA367100 (Hs)
Pharos Q9HC97 (Hs)
RefSeq Nucleotide NM_005301 (Hs), NM_022320 (Mm), NM_001037359 (Rn)
RefSeq Protein NP_005292 (Hs), NP_071715 (Mm), NP_001032436 (Rn)
UniProtKB Q9HC97 (Hs), Q9ES90 (Mm), Q33BM1 (Rn)
Wikipedia GPR35 (Hs)
Natural/Endogenous Ligands Click here for help
kynurenic acid
2-oleoyl-LPA
Comments: Proposed ligands, single publications

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 83 [PMID: 23888932] Small molecule or natural product Hs Agonist 9.2 pKi 16
⤷ pKi 9.2 (Ki 5.9x10-10 M) [16]
Description: In a radioligand competition binding assay using membranes prepared from CHO cells recombinantly expressing human GPR35.
lodoxamide Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 9.0 pEC50 12
⤷ pEC50 9.0 (EC50 1x10-9 M) [12]
Description: In an AP-TGF-α shedding assay using GPR35 expressing HEK293 cells.
zaprinast Small molecule or natural product Rn Agonist 7.8 pEC50 15
⤷ pEC50 7.8 [15]
2-oleoyl-LPA Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Hs Agonist 7.3 – 7.5 pEC50 10
⤷ pEC50 7.3 – 7.5 [10]
pamoic acid Small molecule or natural product Ligand has a PDB structure Hs Agonist 7.3 pEC50 5
⤷ pEC50 7.3 [5]
zaprinast Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.1 pEC50 15
⤷ pEC50 6.1 [15]
furosemide Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 5.2 – 5.6 pEC50 18
⤷ pEC50 5.2 – 5.6 [18]
bumetanide Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Agonist 5.0 – 5.5 pEC50 18
⤷ pEC50 5.0 – 5.5 [18]
kynurenic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Rn Agonist 5.2 pEC50 17
⤷ pEC50 5.2 [17]
kynurenic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Mm Agonist 5.0 pEC50 17
⤷ pEC50 5.0 [17]
kynurenic acid Small molecule or natural product Ligand is endogenous in the given species Ligand has a PDB structure Hs Agonist 3.9 – 4.4 pEC50 14,17
⤷ pEC50 3.9 – 4.4 [14,17]
pamoic acid Small molecule or natural product Ligand has a PDB structure Rn Agonist 3.0 – 5.0 pEC50 5
⤷ pEC50 3.0 – 5.0 [5]
CXCL17 {Sp: Human} Peptide Immunopharmacology Ligand Hs Agonist - - 7
⤷ [7]
Description: As assessed by ability to induce GRR35-dependent calcium flux.
View species-specific agonist tables
Agonist Comments
Wang et al. [17] first reported that kynurenic acid was an agonist of GPR35; this observation has since been replicated in functional assays releasing interleukin 4 [2] and in a β-arrestin assay [14], but controversy remains whether the endogenous ligand reaches sufficient tissue concentrations to activate the receptor [6]. 2-Acyl lysophosphatidic acid (2-oleoyl-LPA) has also been proposed as an endogenous ligand [10] but these results were not replicated in a recent β-arrestin assay [14]. Zaprinast, a cyclic GMP-selective phosphodiesterase (PDE5A/PDE6) inhibitor, has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signalling [14-15]. GPR35 is also activated by the loop diuretic drugs bumetanide and furosemide and the pharmaceutical adjunct pamoic acid [8,19].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CID2745687 Small molecule or natural product Hs Antagonist 7.4 – 7.9 pKi 16,19
⤷ pKi 7.9 (Ki 1.28x10-8 M) [19]
Description: Antagonism of the GPR35 response to 1 μM pamoic acid in a βarrestin2-GFP trafficking assay.
pKi 7.4 (Ki 4.22x10-8 M) [16]
Description: In a competition radiologand binding assay membranes preapred from CHO cells recombinantly expressing human GPR35.
CID2745687 Small molecule or natural product Hs Antagonist 5.0 – 6.7 pIC50 16
⤷ pIC50 6.7 (IC50 2x10-7 M) [16]
Description: Antagonism of zaprinast-mediated activation of GPR35 in a β-arrestin assay.
pIC50 5.0 (IC50 1.04x10-5 M) [16]
Description: Antagonism of zaprinast-mediated activation of GPR35 in a dynamic mass redistribution assay.
Immunopharmacology Comments
GPR35 is expressed by dendritic cells, macrophages, and granulocytes, all of which show chemotactic response to CXCL17 [13]. It is unclear whether the migration stimulatory response to CXCL17 is mediated by direct interaction with GPR35, and work by Park et al. (2017) indicates that this response is in fact not GPR35-dependent, at least in THP-1 cells [12].
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
Immuno Process:  Chemotaxis & migration
Immuno Process:  Inflammation
Tissue Distribution Click here for help
Peripheral leukocytes, spleen, small intestine, colon, stomach
Expression level:  High
Species:  Human
Technique:  qRT-PCR
References:  17
iNKT cells
Expression level:  High
Species:  Human
Technique:  Semi-quantitative RT-PCR, Western blot, immunofluorescence, confocal microscopy
References:  2
Duodenum, ileum, colon
Species:  Mouse
Technique:  in situ hybridisation
References:  17
Spleen, gastrointestinal tract (duodenum, jejunum, ileum, cecum, colon, and rectum)
Expression level:  High
Species:  Mouse
Technique:  qRT-PCR
References:  17
Intestine.
Species:  Rat
Technique:  Northern blot.
References:  9
Lung, stomach, small intestine, colon, skeletal muscle, uterus, brain, cerebrum, heart, liver, bladder, and spinal cord
Species:  Rat
Technique:  Semi-quantitative RT-PCR
References:  15
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Primary sclerosing cholangitis
Orphanet: ORPHA171
References:  1
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  A25T
Global MAF (%):  1
Subpopulation MAF (%):  EUR: 3
Minor allele count:  A=0.009/20
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  VAR_013601, rs35146537
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  V76M
Global MAF (%):  1
Subpopulation MAF (%):  AFR|AMR: 6|1
Minor allele count:  A=0.014/31
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  VAR_033467, rs13387859
Validation:  1000 Genomes, HapMap
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  R125S
Global MAF (%):  2
Subpopulation MAF (%):  AFR|AMR|EUR: 1|1|3
Minor allele count:  A=0.016/35
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession:  VAR_013604, rs34778053
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  T108M
Global MAF (%):  16
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 20|14|9|19
Minor allele count:  T=0.155/339
SNP accession:  VAR_013603, rs3749171
Validation:  1000 Genomes, HapMap
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  T253M
Global MAF (%):  4
Subpopulation MAF (%):  AMR|ASN|EUR: 4|1|10
Minor allele count:  T=0.044/96
SNP accession:  VAR_013605, rs12468485
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  S294R
Global MAF (%):  50
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 20|44|69|57
Minor allele count:  C=0.498/1088
SNP accession:  VAR_013606, rs3749172
Validation:  1000 Genomes, Frequency, Multiple observations
References:  3,9,11
General Comments
Proposed ligand (kynurenic acid), supported by one publication [17].

References

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1. Ellinghaus D, Folseraas T, Holm K, Ellinghaus E, Melum E, Balschun T, Laerdahl JK, Shiryaev A, Gotthardt DN, Weismüller TJ et al.. (2013) Genome-wide association analysis in primary sclerosing cholangitis and ulcerative colitis identifies risk loci at GPR35 and TCF4. Hepatology, 58 (3): 1074-83. [PMID:22821403]

2. Fallarini S, Magliulo L, Paoletti T, de Lalla C, Lombardi G. (2010) Expression of functional GPR35 in human iNKT cells. Biochem Biophys Res Commun, 398 (3): 420-5. [PMID:20599711]

3. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P et al.. (2004) The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res, 14 (10B): 2121-7. [PMID:15489334]

4. Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE et al.. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet, 26 (2): 163-75. [PMID:11017071]

5. Jenkins L, Brea J, Smith NJ, Hudson BD, Reilly G, Bryant NJ, Castro M, Loza MI, Milligan G. (2010) Identification of novel species-selective agonists of the G-protein-coupled receptor GPR35 that promote recruitment of β-arrestin-2 and activate Gα13. Biochem J, 432 (3): 451-9. [PMID:20919992]

6. Kuc D, Zgrajka W, Parada-Turska J, Urbanik-Sypniewska T, Turski WA. (2008) Micromolar concentration of kynurenic acid in rat small intestine. Amino Acids, 35 (2): 503-5. [PMID:18235993]

7. Maravillas-Montero JL, Burkhardt AM, Hevezi PA, Carnevale CD, Smit MJ, Zlotnik A. (2015) Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17. J Immunol, 194 (1): 29-33. [PMID:25411203]

8. Neubig RR. (2010) Mind your salts: when the inactive constituent isn't. Mol Pharmacol, 78 (4): 558-9. [PMID:20651116]

9. O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski Jr LF, George SR. (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics, 47 (2): 310-3. [PMID:9479505]

10. Oka S, Ota R, Shima M, Yamashita A, Sugiura T. (2010) GPR35 is a novel lysophosphatidic acid receptor. Biochem Biophys Res Commun, 395 (2): 232-7. [PMID:20361937]

11. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K et al.. (2004) Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet, 36 (1): 40-5. [PMID:14702039]

12. Park SJ, Lee SJ, Nam SY, Im DS. (2018) GPR35 mediates lodoxamide-induced migration inhibitory response but not CXCL17-induced migration stimulatory response in THP-1 cells; is GPR35 a receptor for CXCL17?. Br J Pharmacol, 175 (1): 154-161. [PMID:29068046]

13. Pisabarro MT, Leung B, Kwong M, Corpuz R, Frantz GD, Chiang N, Vandlen R, Diehl LJ, Skelton N, Kim HS et al.. (2006) Cutting edge: novel human dendritic cell- and monocyte-attracting chemokine-like protein identified by fold recognition methods. J Immunol, 176 (4): 2069-73. [PMID:16455961]

14. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

15. Taniguchi Y, Tonai-Kachi H, Shinjo K. (2006) Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35. FEBS Lett, 580 (21): 5003-8. [PMID:16934253]

16. Thimm D, Funke M, Meyer A, Müller CE. (2013) 6-Bromo-8-(4-[(3)H]methoxybenzamido)-4-oxo-4H-chromene-2-carboxylic Acid: a powerful tool for studying orphan G protein-coupled receptor GPR35. J Med Chem, 56 (17): 7084-99. [PMID:23888932]

17. Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, Ling L. (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem, 281 (31): 22021-8. [PMID:16754668]

18. Yang Y, Fu A, Wu X, Reagan JD. (2012) GPR35 is a target of the loop diuretic drugs bumetanide and furosemide. Pharmacology, 89 (1-2): 13-7. [PMID:22236570]

19. Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, Seltzman HH, Reggio PH, Heynen-Genel S, Sauer M, Chung TD, Bai Y, Chen W, Caron MG, Barak LS, Abood ME. (2010) Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity. Mol Pharmacol, 78 (4): 560-8. [PMID:20826425]

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