Zinc Released from Injured Cells Is Acting via the Zn2+-sensing Receptor, ZnR, to Trigger Signaling Leading to Epithelial Repair

Sharir, Haleli; Zinger, Anna; Nevo, Andrey; Sekler, Israel; Hershfinkel, Michal

doi:10.1074/jbc.m110.107490

Cited by 96 publications

(127 citation statements)

References 79 publications

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“…We therefore established an siRNA silencing paradigm in which we silenced the expression of GPR39 and determined the signaling pathway activated by Zn 2+ (Besser et al 2009). In several experiments we have shown that ZnR activity is mediated by GPR39 in keratinocytes, colonocytes, salivary gland ductal cells, and prostate cancer cells as well as in neurons (Besser et al 2009;Sharir et al 2010;Cohen et al 2012a, b;Asraf et al 2014). In agreement, we monitored loss of ZnR-dependent signaling in native colon tissue and hippocampal CA3 neurons (Chorin et al 2011;Cohen et al 2012a, b).…”

Section: Gpr39 Is the Molecular Moiety Of Znrsupporting

confidence: 78%

“…Although an antimicrobial effect was suggested as a role for Zn 2+ during injury, subsequent studies identified Zn 2+ -dependent signaling that is linked to enhanced proliferation and migration also in keratinocytes. Extracellular Zn 2+ , at the concentrations found in the epidermis and released during injury, triggers Ca 2+ release from thapsigargin-sensitive stores (Sharir et al 2010). The response to Zn 2+ is mediated through a Gαq-coupled receptor, ZnR/GPR39, which activates PLC and the IP 3 pathway and the downstream MAP kinase.…”

Section: Keratinocytes Of the Skinmentioning

confidence: 99%

“…Changes in extracellular Zn 2+ may also occur following the release of this ion from injured cells. For example, following injury of keratinocytic cells, endogenous Zn 2+ is released and may act as a paracrine agonist to a Zn 2+ -sensing receptor ZnR, leading to activation of intracellular signaling pathways associated with wound healing (Sharir et al 2010). These transient changes are quickly reversed either by re-uptake of Zn 2+ via an extensive transporter system consisting of Zip and ZnT proteins or by the buffering of free Zn 2+ by proteins such as metallothioneins (Vasak 2005;Krezel and Maret 2006;Sekler et al 2007;Fukada et al 2011).…”

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confidence: 99%

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The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

Hershfinkel

2014

Zinc Signals in Cellular Functions and Disorders

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The structural role of Zn 2+ in stabilizing numerous enzymes and zinc fingers of transcription factors has been well established for several decades. Therefore, the major effects of this metal ion on growth, development, and cognitive function were not surprising. The importance of cellular homeostasis of Zn 2+ is underlined by the identification of more than 20 proteins involved in transport of Zn 2+ into the cytoplasm and various organelles. In the past decade, evidence for a signaling role of Zn 2+ is emerging, suggesting this ion acts as a first and second messenger. Thus, transient changes in extracellular and intracellular Zn 2+ were monitored and Zn 2+ -dependent regulation of multiple signaling pathways was shown. We have identified the function of ZnR, a Gq protein-coupled receptor that triggers the release of Ca 2+ via the IP3 pathway. This ZnR-dependent signaling regulates cellular pathways involved in survival and proliferation, such as the MAP and PI3 kinase pathways, as well as modulation of ion transport systems such as the Na + /H + exchanger or the K + /Cl À co-transporter. The GPR39 was then shown to mediate extracellular Zn 2+ -dependent ZnR signaling. Here we discuss the major role of ZnR/GPR39 as the link between extracellular Zn 2+ and intracellular signaling pathways regulating the physiological function of epithelial and neuronal cells. A major future challenge will be to identify the role of ZnR/GPR39 in diseases linked to Zn 2+ dyshomeostasis.

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Section: Gpr39 Is the Molecular Moiety Of Znrsupporting

confidence: 78%

Section: Keratinocytes Of the Skinmentioning

confidence: 99%

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confidence: 99%

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The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

Hershfinkel

2014

Zinc Signals in Cellular Functions and Disorders

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“…Consistently, zinc supplementation to Crohn's disease patients during clinical remission or in animal models of experimental colitis reduced intestinal permeability and mucosal damage [12][13][14][15]. A specific Zn 2þ sensing receptor (ZnR) was functionally described in this tissue [16,17] and was later associated with GPR39 as the molecular moiety mediating its activity [18,19]. The ZnR/GPR39 triggers cellular Ca 2þ signalling pathways and enhances cell proliferation, differentiation and survival [20].…”

Section: Introductionmentioning

confidence: 99%

The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis

Sunuwar¹,

Medini²,

Cohen³

et al. 2016

Phil. Trans. R. Soc. B

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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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Zinc Released from Injured Cells Is Acting via the Zn2+-sensing Receptor, ZnR, to Trigger Signaling Leading to Epithelial Repair

Cited by 96 publications

References 79 publications

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

The Zinc-Sensing Receptor, ZnR/GPR39: Signaling and Significance

The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis

Zinc Signaling by “Zinc Wave”

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