GPR39 signaling is stimulated by zinc ions but not by obestatin.
GPR39 is an orphan member of the ghrelin receptor family that recently was suggested to be the receptor for obestatin, a peptide derived from the ghrelin precursor. Here, we compare the effect of obestatin to the effect of Zn(2+) on signal transduction and study the effect of obestatin on food intake. Although Zn(2+) stimulated inositol phosphate turnover, cAMP production, arrestin mobilization, as well as cAMP response element-dependent and serum response element-dependent transcriptional activity in GPR39-expressing cells as opposed to mock-transfected cells, no reproducible effect was obtained with obestatin in the GPR39-expressing cells. Moreover, no specific binding of obestatin could be detected in two different types of GPR39-expressing cells using three different radioiodinated forms of obestatin. By quantitative PCR analysis, GPR39 expression was readily detected in peripheral organs such as duodenum and kidney but not in the pituitary and hypothalamus, i.e. presumed central target organs for obestatin. Obestatin had no significant and reproducible effect on acute food intake in either freely fed or fasted lean mice. It is concluded that GPR39 is probably not the obestatin receptor. In contrast, the potency and efficacy of Zn(2+) in respect of activating signaling indicates that this metal ion could be a physiologically relevant agonist or modulator of GPR39.
Holst
Birgitte
B
Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
Egerod
Kristoffer L
KL
Schild
Enrico
E
Vickers
Steve P
SP
Cheetham
Sharon
S
Gerlach
Lars-Ole
LO
Storjohann
Laura
L
Stidsen
Carsten E
CE
Jones
Rob
R
Beck-Sickinger
Annette G
AG
Schwartz
Thue W
TW
D000818:Animals; D019393:Arrestin / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D015870:Gene Expression / Q000502:physiology; D017930:Genes, Reporter; D054439:Ghrelin; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D036361:Peptide Hormones / Q000378:metabolism* / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014316:Tritium; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology
D019393:Arrestin; D004268:DNA-Binding Proteins; C495797:GPR39 protein, human; D054439:Ghrelin; D007295:Inositol Phosphates; D036361:Peptide Hormones; D043562:Receptors, G-Protein-Coupled; C502774:SRE protein, human; D014157:Transcription Factors; C505799:obestatin, human; D014316:Tritium; D000242:Cyclic AMP; D008156:Luciferases; C045073:Cre recombinase; D019426:Integrases; D015032:Zinc