GPR39 Signaling Is Stimulated by Zinc Ions But Not by Obestatin

Abstract

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.

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…However, later studies were unable to repeat the results (Holst et al, 2007;Lauwers et al, 2006). Instead, Zn 2+ was suggested as a ligand for GPR39 (Holst et al, 2007). Activation of GPR39 increases cAMP accumulation and IP 3 turnover, suggesting that both the G s and G q pathways are involved.…”

“…Obestatin, which is a peptide derived from the ghrelin precursor, was recently suggested as a ligand for GPR39 (Zhang et al, 2005). However, later studies were unable to repeat the results (Holst et al, 2007;Lauwers et al, 2006). Instead, Zn 2+ was suggested as a ligand for GPR39 (Holst et al, 2007).…”

Plasma obestatin levels are lower in obese and post-gastrectomy subjects, but do not change in response to a meal

“…6 Since the original study, however, two other groups have failed to activate the GPR39 receptor with obestatin. 7,8 Initial studies showed that obestatin has opposing effects to ghrelin. When given centrally and peripherally to mice, it resulted in decreased food intake and suppressed gastric emptying.…”

Discovery of 2-Pyridylpyrimidines as the First Orally Bioavailable GPR39 Agonists

“…GPR39 is known to signal through Gαs in addition to Gαq. 4 Thus, we tested compounds in a HEK293 cell line overexpressing the human GPR39 receptor and used forskolin as a reference compound to measure the maximal cAMP release. All compounds were active in Gαs signaling, with compound 3 as the most active both in terms of EC 50 value and maximal efficacy.…”