GPR39

Target id: 105

Nomenclature: GPR39

Family: Class A Orphans

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

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

   GtoImmuPdb view: OFF :     Currently no data for GPR39 in GtoImmuPdb

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 453 2q21-q22 GPR39 G protein-coupled receptor 39
Mouse 7 456 1 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
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
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Comments: Proposed ligands, single publications, but results for obestatin could not be repeated and have since been retracted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
Ligand Sp. Action Affinity Units Reference
compound 15 [PMID: 25313322] Hs Full agonist 9.1 pEC50 13
pEC50 9.1 (EC50 8x10-10 M) [13]
compound 1 [PMID: 24900608] Hs Full agonist 4.9 – 7.2 pEC50 2
pEC50 4.9 – 7.2 (EC50 1.2x10-5 – 5.9x10-8 M) [2]
Zn2+ Hs Agonist - - 6
[6]
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
Adenylate 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

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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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Physiological Consequences of Altering Gene Expression
Acceleration of gastric emptying, more effective transit and expulsion of fecal pellets, greater volume of gastric secretion, higher mature body weight and fat composition and increased cholesterol levels.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  11
Gpr39(-/-) mice displayed normal insulin sensitivity but moderately impaired glucose tolerance, decreased plasma insulin response to oral glucose, normal islet architecture, reduced expression of Pdx-1 and Hnf-1alpha. Isolated, perifused islets from Gpr39 null mice secreted less insulin in response to glucose stimulation than islets from wild-type littermates.
Species:  Mouse
Tissue: 
Technique:  Gene knockout
References:  5,15
Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism
Species:  Mouse
Tissue:  Fat
Technique:  Gene knockouts
References:  12
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0001664 abnormal digestion PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0006003 abnormal large intestinal transit time PMID: 17030183 
Gpr39tm1Dgen Gpr39tm1Dgen/Gpr39tm1Dgen
B6.129P2-Gpr39
MGI:1918361  MP:0005215 abnormal pancreatic islet morphology PMID: 19213841 
Gpr39tm1Dgen Gpr39tm1Dgen/Gpr39tm1Dgen
B6.129P2-Gpr39
MGI:1918361  MP:0002727 decreased circulating insulin level PMID: 19213841 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0003910 decreased eating behavior PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0003961 decreased lean body mass PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0003883 enlarged stomach PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0000503 excessive digestive secretion PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0001260 increased body weight PMID: 17030183 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0005178 increased circulating cholesterol level PMID: 17030183 
Gpr39tm1Dgen Gpr39tm1Dgen/Gpr39tm1Dgen
B6.129P2-Gpr39
MGI:1918361  MP:0005559 increased circulating glucose level PMID: 19213841 
Gpr39tm1Lex Gpr39tm1Lex/Gpr39tm1Lex
involves: 129S5/SvEvBrd * C57BL/6
MGI:1918361  MP:0005458 increased percent body fat PMID: 17030183 
Biologically Significant Variants
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  A50V
SNP accession: 
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  R390C
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
General Comments
For retraction of obestatin as a ligand for GPR39 see [17]

References

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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 Lett4 (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". Science315 (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. Endocrinology150 (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. Endocrinology148: 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. Genomics46: 426-434. [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. Gastroenterology131 (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,  [Epub ahead of print]. [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 Lett5 (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. Endocrinology148 (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". Science315 (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. Science310: 996-999. [PMID:16284174]

Contributors

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How to cite this page

Laura Storjohann.
Class A Orphans: GPR39. Last modified on 30/07/2015. Accessed on 16/12/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=105.