Top ▲
Target not currently curated in GtoImmuPdb
Target id: 105
Nomenclature: GPR39
Family: Class A Orphans
This receptor has a proposed ligand; see the Latest Pairings page for more information.
Gene and Protein Information  |
||||||
| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 453 | 2q21.2 | GPR39 | G protein-coupled receptor 39 | |
| Mouse | 7 | 456 | 1 E2.3-E3 | Gpr39 | G protein-coupled receptor 39 | |
| Rat | 7 | - | 13q11 | Gpr39 | G protein-coupled receptor 39 | |
| Database Links |
|
| Specialist databases | |
| GPCRdb | gpr39_human (Hs), gpr39_mouse (Mm) |
| Other databases | |
| Alphafold | O43194 (Hs), Q5U431 (Mm) |
| ChEMBL Target | CHEMBL3091266 (Hs), CHEMBL3341584 (Mm) |
| Ensembl Gene | ENSG00000183840 (Hs), ENSMUSG00000026343 (Mm), ENSRNOG00000021586 (Rn) |
| Entrez Gene | 2863 (Hs), 71111 (Mm), 288995 (Rn) |
| Human Protein Atlas | ENSG00000183840 (Hs) |
| KEGG Gene | hsa:2863 (Hs), mmu:71111 (Mm), rno:288995 (Rn) |
| OMIM | 602886 (Hs) |
| Pharos | O43194 (Hs) |
| RefSeq Nucleotide | NM_001508 (Hs), NM_027677 (Mm), NM_001100943 (Rn), NM_001114392 (Rn) |
| RefSeq Protein | NP_001499 (Hs), NP_081953 (Mm), NP_001107864 (Rn), NP_001094413 (Rn) |
| UniProtKB | O43194 (Hs), Q5U431 (Mm) |
| Wikipedia | GPR39 (Hs) |
| Natural/Endogenous Ligands |
| obestatin {Sp: Human} , obestatin {Sp: Mouse, Rat} |
| Zn2+ |
| Comments: Proposed ligands, single publications, but results for obestatin could not be repeated and have since been retracted |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Holst et al. (2007) first reported Zn2+ as a potent and efficacious agonist of human GPR39 with an EC50 of ~ 30 µM [6,8]. This has been independently confirmed and shown to be similar also for mouse and rat GPR39 [16]. It has been reported that a fragment from the ghrelin precursor called obestatin was an agonist for GPR39 [18]. However several independent groups have been unable to replicate this [3,6,9,15]. The original authors have since confirmed that they could not reproduce their findings on obestatin binding and activation of GPR39 receptors in vitro [17]. For a list of other 2-pyridylpyrimidine agonist compounds of GPR39 please see [13]. A series of cyclohexyl-methyl aminopyrimidine chemotype compounds were found to induce inositol phosphate generation through agonist action on GPR39 [1]. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary Transduction Mechanisms
|
|
| Transducer | Effector/Response |
| Gq/G11 family | Phospholipase C stimulation |
| Comments: GPR39 is constitutively active and can be further activated by zinc ions, as seen by measuring inositol phosphate accumulation in transient or stable transfections in COS-7, CHO-K1 or HEK-293 cells compared to mock-transfected cells [7,14,16]. | |
| References: 7 | |
| Secondary Transduction Mechanisms |
|
| Transducer | Effector/Response |
|
Gs family G12/G13 family |
Adenylyl cyclase stimulation |
| Comments: GPR39 activation has been shown to increase cAMP via Gαs [6,18] and also to stimulate serum responsive element (SRE) transcriptional activity in a reporter gene assay, at least partially through Gα12/13 [6]. | |
| References: 7 | |
| Tissue Distribution Comments | |
| In the original paper reporting the cloning of GPR39 [10] analyzed expression by Northern blot which suggested a broad distribution in multiple areas of the central nervous system as well as in gastrointestinal tract and pancreas. However, it now seems that GPR39 is not expressed in the brain, but is rather restricted to liver, stomach, pancreas, colon and adipose tissues [4]. |
| Expression Datasets |
|
|
| Physiological Consequences of Altering Gene Expression
|
||||||||||
|
||||||||||
|
||||||||||
|
| Phenotypes, Alleles and Disease Models
|
Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Biologically Significant Variants
|
||||||||||
|
||||||||||
|
| General Comments |
| For retraction of obestatin as a ligand for GPR39 see [17] |
1. Bassilana F, Carlson A, DaSilva JA, Grosshans B, Vidal S, Beck V, Wilmeringwetter B, Llamas LA, Showalter TB, Rigollier P et al.. (2014) Target identification for a Hedgehog pathway inhibitor reveals the receptor GPR39. Nat Chem Biol, 10 (5): 343-9. [PMID:24633354]
2. Boehm M, Hepworth D, Loria PM, Norquay LD, Filipski KJ, Chin JE, Cameron KO, Brenner M, Bonnette P, Cabral S et al.. (2013) Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example. ACS Med Chem Lett, 4 (11): 1079-84. [PMID:24900608]
3. Chartrel N, Alvear-Perez R, Leprince J, Iturrioz X, Reaux-Le Goazigo A, Audinot V, Chomarat P, Coge F, Nosjean O, Rodriguez M, Galizzi JP, Boutin JA, Vaudry H, Llorens-Cortes C. (2007) Comment on "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake". Science, 315 (5813): 766; author reply 766. [PMID:17289961]
4. Egerod KL, Holst B, Petersen PS, Hansen JB, Mulder J, Hökfelt T, Schwartz TW. (2007) GPR39 splice variants versus antisense gene LYPD1: expression and regulation in gastrointestinal tract, endocrine pancreas, liver, and white adipose tissue. Mol Endocrinol, 21 (7): 1685-98. [PMID:17488974]
5. Holst B, Egerod KL, Jin C, Petersen PS, Østergaard MV, Hald J, Sprinkel AM, Størling J, Mandrup-Poulsen T, Holst JJ, Thams P, Orskov C, Wierup N, Sundler F, Madsen OD, Schwartz TW. (2009) G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction. Endocrinology, 150 (6): 2577-85. [PMID:19213833]
6. Holst B, Egerod KL, Schild E, Vickers SP, Cheetham S, Gerlach LO, Storjohann L, Stidsen CE, Jones R, Beck-Sickinger AG, Schwartz TW. (2007) GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology, 148: 13-20. [PMID:16959833]
7. Holst B, Holliday ND, Bach A, Elling CE, Cox HM, Schwartz TW. (2004) Common structural basis for constitutive activity of the ghrelin receptor family. J Biol Chem, 279 (51): 53806-17. [PMID:15383539]
8. Holst B, Nygaard R, Valentin-Hansen L, Bach A, Engelstoft MS, Petersen PS, Frimurer TM, Schwartz TW. (2010) A conserved aromatic lock for the tryptophan rotameric switch in TM-VI of seven-transmembrane receptors. J Biol Chem, 285 (6): 3973-85. [PMID:19920139]
9. Lauwers E, Landuyt B, Arckens L, Schoofs L, Luyten W. (2006) Obestatin does not activate orphan G protein-coupled receptor GPR39. Biochem Biophys Res Commun, 351 (1): 21-5. [PMID:17054911]
10. McKee KK, Tan CP, Palyha OC, Liu J, Feighner SD, Hreniuk DL, Smith RG, Howard AD, Van der Ploeg LH. (1997) Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics, 46 (3): 426-34. [PMID:9441746]
11. Moechars D, Depoortere I, Moreaux B, de Smet B, Goris I, Hoskens L, Daneels G, Kass S, Ver Donck L, Peeters T, Coulie B. (2006) Altered gastrointestinal and metabolic function in the GPR39-obestatin receptor-knockout mouse. Gastroenterology, 131 (4): 1131-41. [PMID:17030183]
12. Petersen PS, Jin C, Madsen AN, Rasmussen M, Kuhre R, Egerod KL, Nielsen LB, Schwartz TW, Holst B. (2011) Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism. FASEB J, 25 (11): 3803-14. [PMID:21784784]
13. Peukert S, Hughes R, Nunez J, He G, Yan Z, Jain R, Llamas L, Luchansky S, Carlson A, Liang G et al.. (2014) Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists. ACS Med Chem Lett, 5 (10): 1114-8. [PMID:25313322]
14. Storjohann L, Holst B, Schwartz TW. (2008) Molecular mechanism of Zn2+ agonism in the extracellular domain of GPR39. FEBS Lett, 582 (17): 2583-8. [PMID:18588883]
15. Tremblay F, Perreault M, Klaman LD, Tobin JF, Smith E, Gimeno RE. (2007) Normal food intake and body weight in mice lacking the G protein-coupled receptor GPR39. Endocrinology, 148 (2): 501-6. [PMID:17095592]
16. Yasuda S, Miyazaki T, Munechika K, Yamashita M, Ikeda Y, Kamizono A. (2007) Isolation of Zn2+ as an endogenous agonist of GPR39 from fetal bovine serum. J Recept Signal Transduct Res, 27 (4): 235-46. [PMID:17885920]
17. Zhang JV, Klein C, Ren P, Kass S, Ver Donck L, Moechars D, Hsueh AJW. (2007) Response to Comment on "Obestatin, a Peptide Encoded by the Ghrelin Gene, Opposes Ghrelin's Effects on Food Intake". Science, 315 (5813): 766d Technical comment.
18. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ. (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science, 310 (5750): 996-9. [PMID:16284174]
