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

Laxmi Sunuwar, Michal Medini, Limor Cohen, Israel Sekler, Michal Hershfinkel

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

Abstract

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’.

Original languageEnglish
Article number20150420
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume371
Issue number1700
DOIs
StatePublished - 5 Aug 2016

Keywords

  • Ca signalling
  • Colitis
  • Intestinal epithelium
  • Tight junction
  • Zinc
  • ZnR/GPR39

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences

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