title: The zinc sensing receptor, ZnR/GPR39, triggers metabotropic calcium signalling in colonocytes and regulates occludin recovery in experimental colitis.
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 Ca(2+) 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 low expression 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 compared with ZnR/GPR39 KO, 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 in WT 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 Ca(2+) and ATP together to control life and death'.
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Laxmi
authors.initials: L
authors.lastname: Sunuwar
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Medini
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Limor
authors.initials: L
authors.lastname: Cohen
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel sekler@bgu.ac.il.
authors.forename: Israel
authors.identifier: 0000-0002-7550-1550
authors.initials: I
authors.lastname: Sekler
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel hmichal@bgu.ac.il.
authors.forename: Michal
authors.identifier: 0000-0003-1652-1989
authors.initials: M
authors.lastname: Hershfinkel
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D003093:Colitis, Ulcerative / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D015870:Gene Expression; D018345:Mice, Knockout; D062793:Occludin / Q000235:genetics* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism
chemical_list: C512928:GPR39 protein, mouse; D062793:Occludin; C568986:Ocln protein, mouse; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate
keywords: Ca2+ signalling; ZnR/GPR39; colitis; intestinal epithelium; tight junction; zinc