TY - JOUR
T1 - The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occluding recovery in experimental colitis
AU - Sunuwar, Laxmi
AU - Medini, Michal
AU - Cohen, Limor
AU - Sekler, Israel
AU - Hershfinkel, Michal
N1 - Publisher Copyright:
© 2016 The Author(s) Published by the Royal Society. All rights reserved.
PY - 2016/8/5
Y1 - 2016/8/5
N2 - Impaired epithelial barrier function is a hallmark of inflammatory bowel diseases, such as colitis, contributing to diarrhoea and perpetuating inflammation. We show that the zinc sensing receptor, ZnR/GPR39, triggers intracellular Ca2+ signalling in colonocytes thereby inducing occludin expression. Moreover, ZnR/GPR39 is essential for epithelial barrier recovery in the dextran sodium sulfate (DSS) ulcerative colitis model. Loss of ZnR/ GPR39 results in increased susceptibility to DSS-induced inflammation, owing to lowexpression of the tight junction protein occludin and impaired epithelial barrier. Recovery of wild-type (WT) mice from the DSS insult was faster than that of ZnR/GPR39 knockout (KO) mice. Enhanced recovery of the epithelial layer and increased crypt regeneration were observed in WT mice comparedwith ZnR/GPR39KO, suggesting that ZnR/GPR39 is promoting epithelial barrier integrity following DSS insult. Indeed, cell proliferation and apical expression of occludin, following the DSS-induced epithelial erosion, were increased inWT tissue but not in ZnR/GPR39 KO tissue. Importantly, survival following DSS treatment was higher in WT mice compared with ZnR/GPR39 KO mice. Our results support a direct role for ZnR/GPR39 in promoting epithelial renewal and barrier function following DSS treatment, thereby affecting the severity of the disease. We suggest ZnR/GPR39 as a novel therapeutic target that can improve epithelial barrier function in colitis. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’.
AB - Impaired epithelial barrier function is a hallmark of inflammatory bowel diseases, such as colitis, contributing to diarrhoea and perpetuating inflammation. We show that the zinc sensing receptor, ZnR/GPR39, triggers intracellular Ca2+ signalling in colonocytes thereby inducing occludin expression. Moreover, ZnR/GPR39 is essential for epithelial barrier recovery in the dextran sodium sulfate (DSS) ulcerative colitis model. Loss of ZnR/ GPR39 results in increased susceptibility to DSS-induced inflammation, owing to lowexpression of the tight junction protein occludin and impaired epithelial barrier. Recovery of wild-type (WT) mice from the DSS insult was faster than that of ZnR/GPR39 knockout (KO) mice. Enhanced recovery of the epithelial layer and increased crypt regeneration were observed in WT mice comparedwith ZnR/GPR39KO, suggesting that ZnR/GPR39 is promoting epithelial barrier integrity following DSS insult. Indeed, cell proliferation and apical expression of occludin, following the DSS-induced epithelial erosion, were increased inWT tissue but not in ZnR/GPR39 KO tissue. Importantly, survival following DSS treatment was higher in WT mice compared with ZnR/GPR39 KO mice. Our results support a direct role for ZnR/GPR39 in promoting epithelial renewal and barrier function following DSS treatment, thereby affecting the severity of the disease. We suggest ZnR/GPR39 as a novel therapeutic target that can improve epithelial barrier function in colitis. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’.
KW - Ca signalling
KW - Colitis
KW - Intestinal epithelium
KW - Tight junction
KW - Zinc
KW - ZnR/GPR39
UR - http://www.scopus.com/inward/record.url?scp=84977594434&partnerID=8YFLogxK
U2 - 10.1098/rstb.2015.0420
DO - 10.1098/rstb.2015.0420
M3 - Article
AN - SCOPUS:84977594434
SN - 0962-8436
VL - 371
JO - Philosophical Transactions of the Royal Society B: Biological Sciences
JF - Philosophical Transactions of the Royal Society B: Biological Sciences
IS - 1700
M1 - 20150420
ER -