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

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

doi:10.1098/rstb.2015.0420

Cited by 38 publications

(31 citation statements)

References 44 publications

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“…5A). Note that previous studies have indicated that under baseline conditions the histological organization of colon tissue from WT and ZnR/GPR39 KO are similar [34]. Immunofluorescence levels of the labeled proteins were similar in WT and ZnR/GPR39 KO mice, indicating similar expression levels of KCC1 in WT and Zn/GPR39 KO tissues (Fig.…”

Section: Resultssupporting

confidence: 63%

“…We initially used undifferentiated Caco-2 colonocytes that exhibit Zn 2+ -dependent signaling mediated by ZnR/GPR39 via a Gq-dependent pathway (Fig. 2A, B), in agreement with previous studies [33,34]. Importantly, the paradigm that triggers Zn 2+ -dependent ZnR/GPR39 signaling does not induce Zn 2+ permeation into these cells (Fig.…”

Section: Resultssupporting

confidence: 53%

“…Such role for intracellular Zn 2+ may underlie the effects of prolonged incubation at the serosal or mucosal sides [9,15–17] and may play an important role in situation of severe Zn 2+ deficiency in humans. Our studies, using a very brief exposure of the cells to Zn 2+ , link a specific extracellular Zn 2+ sensing mechanism to regulation of signaling and ion transport that may offer an important and sensitive therapeutic target [19,26,33,34,81]. Indeed, we see a significant effect of ZnR/GPR39 knockdown on the fluid accumulation in the CTx model, and this is abolished in the absence of endogenous Zn 2+ or KCC1 activity.…”

Section: Discussionmentioning

confidence: 73%

“…The ZnR/GPR39 is activated by extracellular Zn 2+ at the concentration range physiologically found in the digestive tract. Colon epithelial cells exhibit ZnR/GPR39 activity [20], which controls colonocytes growth and differentiation [20,32–34]. In colonocytes, extracellular Zn 2+ induces ZnR/GPR39 activation that triggers a Gq dependent metabotropic release of Ca 2+ [19,26], and subsequent activation of the mitogen activated protein kinase (MAPK), extracellular regulated ERK1/2, pathway [19].…”

Section: Introductionmentioning

confidence: 99%

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The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

Sunuwar

Asraf

Donowitz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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Section: Resultssupporting

confidence: 63%

Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

Sunuwar

Asraf

Donowitz

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…105 Animal models of colitis and cell culture experiments demonstrate an improvement in pro-inflammatory cytokines with zinc supplementation. 106, 107 In healthy elderly subjects, a randomized controlled trial of 6-months of zinc supplementation (dose 45 mg zinc gluconate per day) versus placebo demonstrated a significant decrease in several pro-inflammatory markers including high-sensitivity C-reactive protein, interleukin-6, macrophage chemoattractant protein 1, and vascular cell adhesion molecule 1.…”

Section: Vitamins and Other Micronutrientsmentioning

confidence: 99%

Modifiable Environmental Factors in Inflammatory Bowel Disease

Burke

Boumitri

Ananthakrishnan

2017

Curr Gastroenterol Rep

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Inflammatory bowel diseases (Crohn’s disease, ulcerative colitis) are believed to arise as a result of a dysregulated immune response to commensal gut microbial flora in a genetically susceptible host. Several environmental factors may influence predisposition to disease or its natural history by modification of both the host immune response and intestinal microbial composition. Proposed environmental influences include tobacco use, diet, antibiotics, vitamin D deficiency, stress, appendectomy, and use of oral contraceptive use. Emerging epidemiologic evidence has confirmed the association of many of these factors with incident disease using prospective data. In addition, laboratory data has supported their mechanistic plausibility and relevance to intestinal inflammation. However, fewer studies have examined their impact on natural history. This article will focus on translating such evidence into clinical practice by a focus on interventional studies that have modified such environmental influences to improve disease outcomes.

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Zinc Transport in the Mammalian Intestine

Hennigar

McClung

2018

Comprehensive Physiology

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Zinc homeostasis is primarily maintained in the proximal small intestine. Sophisticated transport mechanisms maintain zinc homeostasis by controlling the uptake and efflux of zinc in intestinal absorptive epithelial cells. Zrt‐irt‐like proteins (ZIPs) and zinc transporters (ZnTs) function in a coordinated manner to assimilate zinc from the lumen of the small intestine, subcellular compartments within the absorptive epithelial cell, and circulation. This manuscript details zinc transport mechanisms in the mammalian small intestine, along with factors that regulate these processes and consequences of dysregulated zinc transport. © 2019 American Physiological Society. Compr Physiol 9:59‐74, 2019.

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

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

Cited by 38 publications

References 44 publications

The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

The Zn 2+ -sensing receptor, ZnR/GPR39, upregulates colonocytic Cl − absorption, via basolateral KCC1, and reduces fluid loss

Modifiable Environmental Factors in Inflammatory Bowel Disease

Zinc Transport in the Mammalian Intestine

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