Cargando…

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously ident...

Descripción completa

Detalles Bibliográficos
Autores principales: Cohen, Limor, Azriel-Tamir, Hagit, Arotsker, Natan, Sekler, Israel, Hershfinkel, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335870/
https://www.ncbi.nlm.nih.gov/pubmed/22545109
http://dx.doi.org/10.1371/journal.pone.0035482
_version_ 1782230870752493568
author Cohen, Limor
Azriel-Tamir, Hagit
Arotsker, Natan
Sekler, Israel
Hershfinkel, Michal
author_facet Cohen, Limor
Azriel-Tamir, Hagit
Arotsker, Natan
Sekler, Israel
Hershfinkel, Michal
author_sort Cohen, Limor
collection PubMed
description Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn(2+) sensing G-protein coupled receptor (ZnR) that activates Ca(2+) signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn(2+), by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca(2+) release and Zn(2+)-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na(+)/H(+) exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na(+)/H(+) exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn(2+)-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn(2+), acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes.
format Online
Article
Text
id pubmed-3335870
institution National Center for Biotechnology Information
language English
publishDate 2012
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-33358702012-04-27 Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin Cohen, Limor Azriel-Tamir, Hagit Arotsker, Natan Sekler, Israel Hershfinkel, Michal PLoS One Research Article Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn(2+) sensing G-protein coupled receptor (ZnR) that activates Ca(2+) signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn(2+), by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca(2+) release and Zn(2+)-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na(+)/H(+) exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na(+)/H(+) exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn(2+)-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn(2+), acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes. Public Library of Science 2012-04-24 /pmc/articles/PMC3335870/ /pubmed/22545109 http://dx.doi.org/10.1371/journal.pone.0035482 Text en Cohen et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Cohen, Limor
Azriel-Tamir, Hagit
Arotsker, Natan
Sekler, Israel
Hershfinkel, Michal
Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title_full Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title_fullStr Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title_full_unstemmed Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title_short Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin
title_sort zinc sensing receptor signaling, mediated by gpr39, reduces butyrate-induced cell death in ht29 colonocytes via upregulation of clusterin
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335870/
https://www.ncbi.nlm.nih.gov/pubmed/22545109
http://dx.doi.org/10.1371/journal.pone.0035482
work_keys_str_mv AT cohenlimor zincsensingreceptorsignalingmediatedbygpr39reducesbutyrateinducedcelldeathinht29colonocytesviaupregulationofclusterin
AT azrieltamirhagit zincsensingreceptorsignalingmediatedbygpr39reducesbutyrateinducedcelldeathinht29colonocytesviaupregulationofclusterin
AT arotskernatan zincsensingreceptorsignalingmediatedbygpr39reducesbutyrateinducedcelldeathinht29colonocytesviaupregulationofclusterin
AT seklerisrael zincsensingreceptorsignalingmediatedbygpr39reducesbutyrateinducedcelldeathinht29colonocytesviaupregulationofclusterin
AT hershfinkelmichal zincsensingreceptorsignalingmediatedbygpr39reducesbutyrateinducedcelldeathinht29colonocytesviaupregulationofclusterin