Nomenclature: GPR35

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates. 

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

Contents

Gene and Protein Information
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 7 306 9q36 Gpr35 G protein-coupled receptor 35
Previous and Unofficial Names
GPR35
G-protein coupled receptor 35
G protein-coupled receptor 35
Kynurenic acid receptor
KYNA receptor
G-protein coupled receptor 3
Gpr35_predicted
LOC367315
G protein-coupled receptor 35 (predicted)
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
Orphanet Gene
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligand(s)
2-oleoyl-LPA
kynurenic acid
Comments: Proposed ligands, single publications
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
zaprinast Rn Agonist 7.8 pEC50 12
pEC50 7.8 [12]
2-oleoyl-LPA Hs Agonist 7.3 – 7.52 pEC50 9
pEC50 7.3 – 7.52 [9]
pamoic acid Hs Agonist 7.29 pEC50 5
pEC50 7.29 [5]
zaprinast Hs Agonist 6.1 pEC50 12
pEC50 6.1 [12]
furosemide Hs Agonist 5.21 – 5.63 pEC50 14
pEC50 5.21 – 5.63 [14]
bumetanide Hs Agonist 5.0 – 5.54 pEC50 14
pEC50 5.0 – 5.54 [14]
kynurenic acid Rn Agonist 5.15 pEC50 13
pEC50 5.15 [13]
kynurenic acid Mm Agonist 4.96 pEC50 13
pEC50 4.96 [13]
kynurenic acid Hs Agonist 3.9 – 4.41 pEC50 11,13
pEC50 3.9 – 4.41 [11,13]
pamoic acid Rn Agonist 3.0 – 5.0 pEC50 5
pEC50 3.0 – 5.0 [5]
View species-specific agonist tables
Agonist Comments
Wang et al. [13] first reported that kynurenic acid (IUPHAR-DB ID no. 2918) was an agonist of GPR35; this observation has since been replicated in functional assays releasing interleukin 4 [2] and in a β-arrestin assay [11], but controversy remains whether the endogenous ligand reaches sufficient tissue concentrations to activate the receptor [6]. 2-Acyl lysophosphatidic acid (2-oleoyl-LPA; IUPHAR-DB ID no. 2936) has also been proposed as an endogenous ligand [9] but these results were not replicated in in a recent β-arrestin assay [11]. Zaprinast (IUPHAR-DB ID no. 2919), a cyclic GMP-selective phosphodiesterase (PDE5A/PDE6) inhibitor, has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signaliing [11-12]. GPR35 is also activated by the loop diuretic drugs bumetanide and furosemide [10] and the pharmaceutical adjunct pamoic acid [7,15].
Tissue Distribution
Peripheral leukocytes, spleen, small intestine, colon, stomach
Expression level:  High
Species:  Human
Technique:  qRT-PCR
References:  13
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:  13
Spleen, gastrointestinal tract (duodenum, jejunum, ileum, cecum, colon, and rectum)
Expression level:  High
Species:  Mouse
Technique:  qRT-PCR
References:  13
Intestine.
Species:  Rat
Technique:  Northern blot.
References:  8
Lung, stomach, small intestine, colon, skeletal muscle, uterus, brain, cerebrum, heart, liver, bladder, and spinal cord
Species:  Rat
Technique:  Semi-quantitative RT-PCR
References:  12
Expression Datasets

Show »

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
Disease:  Primary sclerosing cholangitis
Orphanet:  171
References:  1
Mutations not determined
Biologically Significant Variants
Type:  SNP
Species:  Human
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: 
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  SNP
Species:  Human
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: 
Validation:  1000 Genomes, HapMap
References:  4
Type:  SNP
Species:  Human
Change:  T108M
Global MAF (%):  16
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 20|14|9|19
Minor allele count:  T=0.155/339
SNP accession: 
Validation:  1000 Genomes, HapMap
References:  4
Type:  SNP
Species:  Human
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: 
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  SNP
Species:  Human
Change:  T253M
Global MAF (%):  4
Subpopulation MAF (%):  AMR|ASN|EUR: 4|1|10
Minor allele count:  T=0.044/96
SNP accession: 
Validation:  1000 Genomes, Frequency, Multiple observations
References:  4
Type:  SNP
Species:  Human
Change:  S294R
Global MAF (%):  50
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 20|44|69|57
Minor allele count:  C=0.498/1088
SNP accession: 
Validation:  1000 Genomes, Frequency, Multiple observations
References:  3,8,10
General Comments
Proposed ligand (kynurenic acid), supported by one publication [13].
Available Assays
DiscoveRx PathHunter® CHO-K1 GPR35 β-Arrestin Cell Line (Cat no. 93-0942C2) more info

REFERENCES

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. Hepatology58 (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,  [Epub ahead of print]. [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 Acids35 (2): 503-5. [PMID:18235993]

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

8. O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, Kolakowski LF, George SR. (1998) Discovery of three novel G-protein-coupled receptor genes. Genomics47: 310-313. [PMID:9479505]

9. 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]

10. 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]

11. 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 Screen18 (5): 599-609. [PMID:23396314]

12. 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]

13. 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]

14. Yang Y, Fu A, Wu X, Reagan JD. (2012) GPR35 is a target of the loop diuretic drugs bumetanide and furosemide. Pharmacology89 (1-2): 13-7. [PMID:22236570]

15. 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]

To cite this database page, please use the following:

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR35. Last modified on 17/03/2014. Accessed on 19/04/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=102.

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