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GPR39 Signaling Is Stimulated by Zinc Ions But Not by Obestatin

Laboratory for Molecular Pharmacology (B.H., K.L.E., L.S., T.W.S.), The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark; Institute of Biochemistry (E.S., A.G.B.-S.), University of Leipzig, 04103 Leipzig, Germany; RenaSci Consultancy Ltd. (S.P.V., S.C., R.J.), Nottingham NG1 1GF, United Kingdom; Department of Diabetes Metabolism (C.E.S.), Novo Nordisk A/S, DK-2760 Maaloev, Denmark; and 7TM Pharma A/S (L.-O.G., T.W.S.), DK-2970 Hørsholm, Denmark

Address all correspondence and requests for reprints to: Thue W. Schwartz, Laboratory for Molecular Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark. E-mail: schwartz{at}molpharm.dk.

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 Zn²⁺ on signal transduction and study the effect of obestatin on food intake. Although Zn²⁺ 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 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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