Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+ Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

Abstract

Extracellular zinc promotes cell proliferation and its deficiency leads to impairment of this process, which is particularly important in epithelial cells. We have recently characterized a zinc-sensing receptor (ZnR) linking extracellular zinc to intracellular release of calcium. In the present study, we addressed the role of extracellular zinc, acting via the ZnR, in regulating the MAP kinase pathway and Na Arrested cell proliferation is a hallmark of zinc deficiency. This is particularly true in gastrointestinal cells (1-4), where insufficient dietary zinc attenuates the renewal of the epithelium leading to severe diarrhea (1). Extracellular zinc has been shown to regulate cell proliferation via the MAP 1 kinase pathway in several cell types (5-7). Although the mitogenic and anti-apoptotic effects of zinc are well recognized (8, 9), and the treatment of severe diarrhea by addition of dietary zinc is common, the direct link between this ion and the cellular mechanisms regulating proliferation is not well understood. It has been suggested that a decrease in intracellular zinc may lead directly to a reduction in activity of various metalloenzymes involved in transcription and cell metabolism (1, 10). Several studies, however, indicate that extracellular zinc acts as a signaling molecule. In tracheal cells, for example, extracellular zinc, through activation of Src, leads to transactivation of EGFR and subsequently to activation of ERK1/2 (11). In fibroblasts, extracellular zinc has been shown to trigger the activation of the PI3K pathway, subsequently leading to the activation of AKT and the S6 kinase (12). The signaling pathways linking extracellular zinc to these proteins and to subsequent regulation of cellular ion, pH or volume homeostasis, however, remain poorly understood.We have recently identified and characterized an extracellular zinc-sensing receptor (ZnR) that triggers, upon exposure to extracellular zinc, the release of Ca 2ϩ from intracellular stores by activation of the IP 3 pathway (13). The pharmacological profile of the calcium response triggered by the ZnR, particularly its sensitivity to the PLC inhibitor, U73122, and the inhibitory effect of the IP 3 receptor blocker, 2-APB, indicates that the ZnR is a G q -coupled receptor (GPCR). Both the G␣ and the G␤␥ dimer of various GPCRs have been linked to activation of the MAP kinase via multiple intracellular pathways (14 -16). In intestinal cells, furthermore, the muscarinic receptor has been shown to play a key role in promoting ion transport through activation of MAP and PI 3-kinase signal transduction (17,18). A role for the ZnR in activation of the MAP kinase pathway is demonstrated in this work.The ZnR was initially characterized in the colonocytic cell line, HT29, where a robust calcium signal was generated following activation of the receptor by changes in the concentration of extracellular Zn 2ϩ (13). Importantly, the Ca 2ϩ response induced by the ZnR in HT29 cells is triggered by ϳ80 M zinc, i.e. within the physiological range of zinc conc...

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

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l-Threonine Regulates G1/S Phase Transition of Mouse Embryonic Stem Cells via PI3K/Akt, MAPKs, and mTORC Pathways

“…Cells (E14TG2a and R1) were subsequently pulsed with 1 Ci of inducing cyclin D1 (28). Activation of the PI3K/Akt pathway frequently elicits the activation of other intracellular signaling cascades such as MAPKs (29). In addition, mTOR signaling pathway and downstream molecules such as p70S6K and 4E-BP1 can be stimulated by PI3K/Akt and MAPKs pathways (30,31).…”

Zinc ions upregulate the hormone gastrin via an E-box motif in the proximal gastrin promoter

“…Treatment with extracellular Zn 2C ions has been shown to activate both the MAPK and phosphatidylinositol 3-kinase (PI3K) pathways (Kim et al 2000, Azriel-Tamir et al 2004, Hershfinkel et al 2007). In order to establish which signaling pathway was involved in the stimulation of gastrin expression by Zn 2C ions, the expression of gastrin mRNA and gastrin promoter activity was measured after pretreatment of AGS cells for 30 min with either the PI3K inhibitor LY294002 (10 mM) or the MAPK inhibitor U0126 (10 mM), followed by treatment with 50 mM ZnCl 2 for 16 h in the presence of the same inhibitors.…”