HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 50, 51804-51816, December 10, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/50/51804    most recent M406581200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Azriel-Tamir, H. Articles by Hershfinkel, M. Search for Related Content PubMed PubMed Citation Articles by Azriel-Tamir, H. Articles by Hershfinkel, M. Social Bookmarking                      What's this?

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

Hagit Azriel-Tamir, Haleli Sharir, Betty Schwartz¶, and Michal Hershfinkel||

From the Departments of Morphology and Physiology, Zlotowski Center for Neuroscience and the Cancer Research Center, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel and the ^¶Institute of Biochemistry, Food Science and Nutrition, Faculty of Agricultural, The Hebrew University of Jerusalem, Rehovot 76100, Israel

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⁺/H⁺ exchange in colonocytes. We demonstrate that Ca²⁺ release, mediated by the ZnR, induces phosphorylation of ERK1/2, which is highly metal-specific, mediated by physiological concentrations of extracellular Zn²⁺ but not by Cd²⁺, Fe²⁺, Ni²⁺, or Mn²⁺. Desensitization of the ZnR by Zn²⁺, is followed by 90% inhibition of the Zn²⁺-dependent ERK1/2 phosphorylation, indicating that the ZnR is a principal link between extracellular Zn²⁺ and ERK1/2 activation. Application of both the IP₃ pathway and PI 3-kinase antagonists largely inhibited Zn²⁺-dependent ERK1/2 phosphorylation. The physiological significance of the Zn²⁺-dependent activation of ERK1/2 was addressed by monitoring Na⁺/H⁺ exchanger activity in HT29 cells and in native colon epithelium. Preincubation of the cells with zinc was followed by robust activation of Na⁺/H⁺ exchange, which was eliminated by cariporide (0.5 µM); indicating that zinc enhances the activity of NHE1. Activation of NHE1 by zinc was totally blocked by the ERK1/2 inhibitor, U0126. Prolonged acidification, in contrast, stimulates NHE1 by a distinct pathway that is not affected by extracellular Zn²⁺ or inhibitors of the MAP kinase pathway. Desensitization of ZnR activity eliminates the Zn²⁺-dependent, but not the prolonged acidification-dependent activation of NHE1, indicating that Zn²⁺-dependent activation of H⁺ extrusion is specifically mediated by the ZnR. Our results support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways that affect pH homeostasis in colonocytes. Furthermore activation of both, ERK and NHE1, by extracellular zinc may provide the mechanism linking zinc to enhanced cell proliferation.

Received for publication, June 14, 2004 , and in revised form, September 1, 2004.

^* This work was supported in part by Binational Science Foundation Grant 2001101 (to M. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Morphology, Faculty of Health Sciences, Ben Gurion University, Box 653, Beer-Sheva 84105, Israel. E-mail: hmichal{at}bgu.ac.il.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				E. Ohana, E. Hoch, C. Keasar, T. Kambe, O. Yifrach, M. Hershfinkel, and I. Sekler Identification of the Zn2+ Binding Site and Mode of Operation of a Mammalian Zn2+ Transporter J. Biol. Chem., June 26, 2009; 284(26): 17677 - 17686. [Abstract] [Full Text] [PDF]

				L. Besser, E. Chorin, I. Sekler, W. F. Silverman, S. Atkin, J. T. Russell, and M. Hershfinkel Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus J. Neurosci., March 4, 2009; 29(9): 2890 - 2901. [Abstract] [Full Text] [PDF]

				N. Dubi, L. Gheber, D. Fishman, I. Sekler, and M. Hershfinkel Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells Carcinogenesis, September 1, 2008; 29(9): 1692 - 1700. [Abstract] [Full Text] [PDF]

				S. Bao and D. L. Knoell Zinc modulates airway epithelium susceptibility to death receptor-mediated apoptosis Am J Physiol Lung Cell Mol Physiol, March 1, 2006; 290(3): L433 - L441. [Abstract] [Full Text] [PDF]

				C. Treiber Metals on the Brain Sci. Aging Knowl. Environ., September 7, 2005; 2005(36): pe27 - pe27. [Abstract] [Full Text]