title: The Zn2+-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl-absorption, via basolateral KCC1, and reduces fluid loss.
abstract: Administration of zinc, as a complement to oral rehydration solutions, effectively diminishes duration and severity of diarrhea, but it is not known whether it merely fulfills a nutritional deficiency, or if zinc has a direct role of regulating solute absorption. We show that Zn2+acts via a specific receptor, ZnR/GPR39, to reduce fluid loss. Intestinal fluid secretion triggered by cholera toxin (CTx) was lower in WT mice compared to ZnR/GPR39 KO. In the absence of dietary Zn2+we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn2+and ZnR/GPR39 are both required for a beneficial effect of Zn2+in diarrhea. In primary colonocytes and in Caco-2 colonocytic cells, activation of ZnR/GPR39 enhanced Cl-transport, a critical factor in diarrhea, by upregulating K+/Cl-cotransporter (KCC1) activity. Importantly, we show basolateral expression of KCC1 in mouse and human colonocytes, thus identifying a novel Cl-absorption pathway. Finally, inhibition of KCC-dependent Cl-transport enhanced CTx-induced fluid loss. Altogether, our data indicate that Zn2+acting via ZnR/GPR39 has a direct role in controlling Cl-absorption via upregulation of basolateral KCC1 in the colon. Moreover, colonocytic ZnR/GPR39 and KCC1 reduce water loss during diarrhea and may therefore serve as effective drug targets.
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, 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, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Asraf
authors.affiliation: Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Donowitz
authors.affiliation: Department of Physiology and Cell Biology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.
authors.forename: Israel
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, Israel. Electronic address: hmichal@bgu.ac.il.
authors.forename: Michal
authors.initials: M
authors.lastname: Hershfinkel
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000378:metabolism*; D003967:Diarrhea / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D017136:Ion Transport / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism; D000096922:K Cl- Cotransporters
chemical_list: D002712:Chlorides; D043562:Receptors, G-Protein-Coupled; D027981:Symporters; D015032:Zinc; D000096922:K Cl- Cotransporters; C495797:GPR39 protein, human; C512928:GPR39 protein, mouse
keywords: Diarrhea; K(+)/Cl(−) cotransporter; KCC; Zinc sensing receptor; Zinc signaling; ZnR/GPR39