G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction

Holst, Birgitte; Egerod, Kristoffer L.; Jin, Chunyu; Petersen, P. H.; Østergaard, Morten; Hald, Jacob; Sprinkel, A. M. Ejernaes; Størling, Joachim; Mandrup-Poulsen, Thomas; Holst, Jens J.; Thams, Peter; Ørskov, Cathrine; Wierup, Nils; Sundler, F.; Madsen, Ole; Schwartz, Thue W.

doi:10.1210/en.2008-1250

Cited by 85 publications

(89 citation statements)

References 44 publications

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“…Interestingly, although not coexpressed with insulin-producing b-cells in the pancreas, Ob secretion has been shown in human pancreatic islet cells and in the INS-1E b-cell line, suggesting that, similarly to ghrelin, Ob may act in the pancreas through autocrine/paracrine mechanisms (Granata et al 2008). Besides GPR39 potentially being the receptor of Ob (Zhang et al 2005, Dong et al 2009, its expression has been demonstrated both in human and rodent endocrine pancreas and in b-cell lines (Holst et al 2009, Tremblay et al 2009), raising the possibility of GPR39 ligands directly influencing pancreatic islet activity.…”

Section: Ag Uag and Ob Expression In The Endocrine Pancreasmentioning

confidence: 99%

“…Interestingly, isolated, perfused islets from GPR39 null mice have recently been shown to secrete less insulin in response to glucose stimulation than islets from wild-type littermates (Holst et al 2009). Moreover, GPR39 null mice fed with either a low-fat/ high-sucrose or high-fat/high-sucrose diet show decreased serum insulin levels during an oral glucose tolerance test in the face of unchanged insulin tolerance (Tremblay et al 2009), suggesting that GPR39 is required for insulin secretion and may be a potential target for the treatment of diabetes.…”

Section: Effect Of Ag Uag and Ob On Insulin Secretion In Pancreaticmentioning

confidence: 99%

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Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

Granata

Baragli²,

Settanni³

et al. 2010

Journal of Molecular Endocrinology

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The ghrelin gene peptides include acylated ghrelin (AG), unacylated ghrelin (UAG), and obestatin (Ob). AG, mainly produced by the stomach, exerts its central and peripheral effects through the GH secretagogue receptor type 1a (GHS-R1a). UAG, although devoid of GHS-R1a-binding affinity, is an active peptide, sharing with AG many effects through an unknown receptor. Ob was discovered as the G-protein-coupled receptor 39 (GPR39) ligand; however, its physiological actions remain unclear. The endocrine pancreas is necessary for glucose homeostasis maintenance. AG, UAG, and Ob are expressed in both human and rodent pancreatic islets from fetal to adult life, and the pancreas is the major source of ghrelin in the perinatal period. GHS-R1a and GPR39 expression has been shown in b-cells and islets, as well as specific binding sites for AG, UAG, and Ob. Ghrelin colocalizes with glucagon in a-islet cells, but is also uniquely expressed in 3-islet cells, suggesting a role in islet function and development. Indeed, AG, UAG, and Ob regulate insulin secretion in b-cells and isolated islets, promote b-cell proliferation and survival, inhibit b-cell and human islet cell apoptosis, and modulate the expression of genes that are essential in pancreatic islet cell biology. They even induce b-cell regeneration and prevent diabetes in streptozotocin-treated neonatal rats. The receptor(s) mediating their effects are not fully characterized, and a signaling crosstalk has been suggested. The present review summarizes the newest findings on AG, UAG, and Ob expression in pancreatic islets and the role of these peptides on b-cell development, survival, and function.

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Section: Ag Uag and Ob Expression In The Endocrine Pancreasmentioning

confidence: 99%

Section: Effect Of Ag Uag and Ob On Insulin Secretion In Pancreaticmentioning

confidence: 99%

Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

Granata

Baragli²,

Settanni³

et al. 2010

Journal of Molecular Endocrinology

View full text Add to dashboard Cite

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“…GPR39 has been reported to be associated with type 2 diabetes (Holst et al, 2009;Verhulst et al, 2011) and depression (Młyniec and Nowak, 2015;Młyniec et al, 2015a,b,c). GPR39 has been found to be expressed in mouse intestinal fibroblastlike cells (Zeng et al, 2012), human colon adenocarcinoma HT-29 cells (Yasuda et al, 2007;Cohen et al, 2012Cohen et al, , 2014, rat colon BRIN-BD11 cells (Moran et al, 2016), and mouse pancreatic epithelial NIT-1 cells (Fjellström et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

et al. 2016

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In this study, we identified two previously described kinase inhibitors-3-(4-chloro-2-fluorobenzyl)-2-methyl-N-(3-methyl-1H-pyrazol-agonists by unbiased small-molecule-based screening using a b-arrestin recruitment screening approach (PRESTO-Tango). We characterized the signaling of LY2784544 and GSK2636771 and compared their signaling patterns with a previously described "GPR39-selective"at both canonical and noncanonical signaling pathways. Unexpectedly, all three compounds displayed probe-dependent and pathway-dependent allosteric modulation by concentrations of zinc reported to be physiologic. LY2784544 and GS2636771 at GPR39 in the presence of zinc were generally as potent or more potent than their reported activities against kinases in whole-cell assays. These findings reveal an unexpected role of zinc as an allosteric potentiator of small-molecule-induced activation of GPR39 and expand the list of potential kinase off-targets to include understudied G protein-coupled receptors.

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“…Intercellular Zn communication mediated through the Zn-sensing receptor GPR39 is also involved in regulating epithelial cell repair (Sharir et al 2010) and endocrine pancreatic function (Holst et al 2009). Also supporting the role of Zn as a neurotransmitter, Hosie et al identified two Zn-binding sites and characterized a third in the GABA receptor using site-directed mutagenesis (Hosie et al 2003).…”

Section: Zn Acts As a Neurotransmittermentioning

confidence: 99%

Zinc Signaling by “Zinc Wave”

Nishida

Yamasaki

2014

Zinc Signals in Cellular Functions and Disorders

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Zinc (Zn) is an essential heavy metal for all organisms. Zn homeostasis is maintained in mammalian cells through the activity of Zn transporters and Zn-permeable channels and through metallothionein expression levels. Zn is important in nucleic acid metabolism, cell replication, and tissue growth and repair. Zn deficiency is associated with a wide range of pathological conditions, such as impaired immunity, growth retardation, disorders in brain development, and delayed wound healing. Zn binds and affects the activity of several signaling molecules and of transcription factors that have a Zn-binding motif. However, whether Zn itself, as does calcium, acts as an intracellular signaling molecule has been a point of speculation. Recently, we and other groups have demonstrated that Zn does indeed act as an intracellular signaling molecule, converting extracellular stimuli to intracellular signals and controlling various cell functions. This chapter summarizes our current understanding of Zn signaling, especially with regard to the Zn wave and the role of Zn signaling in immune cells, and discusses how these processes contribute to allergic responses.

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G Protein-Coupled Receptor 39 Deficiency Is Associated with Pancreatic Islet Dysfunction

Cited by 85 publications

References 44 publications

Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

Unraveling the role of the ghrelin gene peptides in the endocrine pancreas

Discovery and Characterization of Novel GPR39 Agonists Allosterically Modulated by Zinc

Zinc Signaling by “Zinc Wave”

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