GPR35

GPR35
Identifiers
Aliases	GPR35, G protein-coupled receptor 35
External IDs	OMIM: 602646; MGI: 1929509; HomoloGene: 3874; GeneCards: GPR35; OMA:GPR35 - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2q37.3 Start 240,605,430 bp[1] End 240,633,159 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 D Start 92,878,587 bp[2] End 92,914,113 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon mucosa of ileum duodenum jejunal mucosa granulocyte right uterine tube monocyte rectum body of stomach mucosa of sigmoid colon Top expressed in zygote lumbar spinal ganglion primary oocyte secondary oocyte neural layer of retina urethra granulocyte esophagus yolk sac colon More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G protein-coupled receptor activity signal transducer activity C-X-C chemokine receptor activity Cellular component integral component of membrane integral component of plasma membrane membrane plasma membrane Biological process G protein-coupled receptor signaling pathway signal transduction cytoskeleton organization positive regulation of cytosolic calcium ion concentration positive regulation of Rho protein signal transduction positive regulation of cytosolic calcium ion concentration involved in phospholipase C-activating G protein-coupled signaling pathway chemokine-mediated signaling pathway negative regulation of voltage-gated calcium channel activity negative regulation of neuronal action potential Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2859 64095 Ensembl ENSG00000178623 ENSMUSG00000026271 UniProt Q9HC97 Q9ES90 RefSeq (mRNA) NM_005301 NM_001195381 NM_001195382 NM_001394730 NM_001104529 NM_001271766 NM_022320 RefSeq (protein) NP_001182310 NP_001182311 NP_005292 NP_001097999 NP_001258695 NP_071715 Location (UCSC) Chr 2: 240.61 – 240.63 Mb Chr 1: 92.88 – 92.91 Mb PubMed search [3] [4]
Wikidata
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G protein-coupled receptor 35 also known as GPR35 is a G protein-coupled receptor which in humans is encoded by the GPR35 gene.^[5] Heightened expression of GPR35 is found in immune and gastrointestinal tissues, including the crypts of Lieberkühn.

Ligands

Endogenous ligands

Although GPR35 is still considered an orphan receptor, there have been attempts to deorphanize it by identifying endogenous molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high potency, a characteristic feature of natural ligands.^[6] The following list includes the most prominent examples:

• kynurenic acid^[7][8]
• LPA species^[7]
• cyclic guanosine monophosphate^[9]
• DHICA^[10]
• T₃^[10]
• reverse T₃^[10]

Synthetic agonists

Other synthetic agonists of GPR35 include:

• cromoglicic acid^[11]
• nedocromil^[11]
• pamoic acid^[7]
• zaprinast^[7][12]
• lodoxamide^[13]
• bufrolin^[13]

Zaprinast is currently the gold standard in the biochemical evaluation of novel synthetic GPR35 agonists, because it remains potent in an animal model. Most other known agonists display high selectivity towards the human GPR35 orthologue. This phenomenon is well established for other GPCRs and complicates the development of pharmaceutical drugs.^[6][14][15]

Antagonists

Antagonists of GPR35 include:

• ML145 (CID-2286812)^[16]
• ML144 (CID-1542103)^[16]

Both ML145 and ML144 unfurl their antagonistic activity through inverse agonism. They are, however, highly species-selective, and practically inactive at the rodent receptor orthologues.^[17]

Clinical significance

Deletion of GPR35 gene may be responsible for brachydactyly mental retardation syndrome and is mutated in 2q37 monosomy and 2q37 deletion syndrome.^[18] In one study GPR35 has been recognised as a potential oncogene in stomach cancer.^[19]

References

1. GRCh38: Ensembl release 89: ENSG00000178623 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026271 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. O'Dowd BF, Nguyen T, Marchese A, Cheng R, Lynch KR, Heng HH, et al. (January 1998). "Discovery of three novel G-protein-coupled receptor genes". Genomics. 47 (2): 310–313. doi:10.1006/geno.1998.5095. PMID 9479505.
6. Divorty N, Mackenzie AE, Nicklin SA, Milligan G (2015-03-10). "G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease". Frontiers in Pharmacology. 6. Frontiers Media SA: 41. doi:10.3389/fphar.2015.00041. PMC 4354270. PMID 25805994.
7. Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, et al. (October 2010). "Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity". Molecular Pharmacology. 78 (4). American Society for Pharmacology & Experimental Therapeutics (ASPET): 560–568. doi:10.1124/mol.110.066746. PMC 2981393. PMID 20826425.
8. Wang J, Simonavicius N, Wu X, Swaminath G, Reagan J, Tian H, et al. (August 2006). "Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35". The Journal of Biological Chemistry. 281 (31): 22021–22028. doi:10.1074/jbc.M603503200. PMID 16754668.free fulltext Archived 2009-02-17 at the Wayback Machine
9. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, et al. (June 2013). "Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors". Journal of Biomolecular Screening. 18 (5). SAGE Publications: 599–609. doi:10.1177/1087057113475480. PMID 23396314.
10. Deng H, Hu H, Fang Y (2012-04-20). "Multiple tyrosine metabolites are GPR35 agonists". Scientific Reports. 2 (1). Springer Nature: 373. Bibcode:2012NatSR...2E.373D. doi:10.1038/srep00373. PMC 3330681. PMID 22523636.
11. Yang Y, Lu JY, Wu X, Summer S, Whoriskey J, Saris C, et al. (2010). "G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium". Pharmacology. 86 (1). S. Karger AG: 1–5. doi:10.1159/000314164. PMID 20559017. S2CID 9421354.
12. Taniguchi Y, Tonai-Kachi H, Shinjo K (September 2006). "Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35". FEBS Letters. 580 (21): 5003–5008. doi:10.1016/j.febslet.2006.08.015. PMID 16934253. S2CID 43142927.
13. MacKenzie AE, Caltabiano G, Kent TC, Jenkins L, McCallum JE, Hudson BD, et al. (January 2014). "The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35". Molecular Pharmacology. 85 (1): 91–104. doi:10.1124/mol.113.089482. PMC 3868900. PMID 24113750.
14. Thimm D, Knospe M, Abdelrahman A, Moutinho M, Alsdorf BB, von Kügelgen I, et al. (September 2013). "Characterization of new G protein-coupled adenine receptors in mouse and hamster". Purinergic Signalling. 9 (3). Springer Nature: 415–426. doi:10.1007/s11302-013-9360-9. PMC 3757137. PMID 23608776.
15. Gütschow M, Schlenk M, Gäb J, Paskaleva M, Alnouri MW, Scolari S, et al. (April 2012). "Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives". Journal of Medicinal Chemistry. 55 (7). American Chemical Society (ACS): 3331–3341. doi:10.1021/jm300029s. PMID 22409573.
16. Heynen-Genel S, Dahl R, Shi S, Sauer M, Hariharan S, Sergienko E, et al. (2010). "Selective GPR35 Antagonists - Probes 1 & 2". Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US). PMID 21433393. Bookshelf ID NBK50703.
17. Jenkins L, Harries N, Lappin JE, MacKenzie AE, Neetoo-Isseljee Z, Southern C, et al. (December 2012). "Antagonists of GPR35 display high species ortholog selectivity and varying modes of action". The Journal of Pharmacology and Experimental Therapeutics. 343 (3). American Society for Pharmacology & Experimental Therapeutics (ASPET): 683–695. doi:10.1124/jpet.112.198945. PMC 3500541. PMID 22967846.
18. Shrimpton AE, Braddock BR, Thomson LL, Stein CK, Hoo JJ (December 2004). "Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype". Clinical Genetics. 66 (6): 537–544. doi:10.1111/j.1399-0004.2004.00363.x. PMID 15521982. S2CID 42975740.
19. Okumura S, Baba H, Kumada T, Nanmoku K, Nakajima H, Nakane Y, et al. (February 2004). "Cloning of a G-protein-coupled receptor that shows an activity to transform NIH3T3 cells and is expressed in gastric cancer cells". Cancer Science. 95 (2): 131–135. doi:10.1111/j.1349-7006.2004.tb03193.x. PMC 11159784. PMID 14965362. S2CID 22753833.