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Submitted on July 12, 2006
Accepted on August 28, 2006
Laboratory for Molecular Pharmacology, The Panum Institute, Blegdamsvej 3, University of Copenhagen, DK-2200 Copenhagen, Denmark (BH, KLE, LS, and TWS); Institute of Biochemistry, University of Leipzig, Bruderstrasse 34, 04103 Leipzig, Germany (ES and AGB-S); RenaSci Consultancy Ltd., BioCity Nottingham, Pennyfoot Street, Nottingham, NG1 1GF, UK (SPV, SC, and RJ); Department of Diabetes Metabolism, Novo Nordisk A/S, Novo Nordisk Park, DK-2760, Maaloev, Denmark (CES); 7TM Pharma A/S, Fremtidsvej 3, DK-2970, Hørsholm, Denmark (LOG and TWS)
* To whom correspondence should be addressed. E-mail: schwartz{at}molpharm.dk.
GPR39 is an orphan member of the ghrelin receptor family which 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 Zn2+ on signal transduction and study the effect of obestatin on food intake. Whereas Zn2+ stimulated inositol phosphate turnover, cAMP production, arrestin mobilization, as well as cAMP response element (CRE) dependent and serum response element (SRE) 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 radio-iodinated forms of obestatin. By QPCR 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 neither freely fed nor fasted lean mice. It is concluded that GPR39 is probably not the obestatin receptor. In contrast, the potency and efficacy of Zn2+ in respect of activating signaling indicates that this metal ion could be a physiologically relevant agonist or modulator of GPR39.
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