The Zn 2+ -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.

Biogenesis of zinc storage granules inDrosophila melanogaster

“…As the Malpighian tubules are typically involved in excretion (Chi et al, 2015;Halberg et al, 2015;Yin et al, 2017), one intriguing possibility is that zinc storage granules provide a source of zinc for the intestinal lumen. In this view, the Malpighian tubule principal cells would have a similar physiological purpose as the intestinal paneth cells in mammals, where the secreted zinc has been implicated in the maintenance of the stem cell niche and epithelial integrity (Geiser et al, 2012;Ohashi et al, 2016;Podany et al, 2016;Sunuwar et al, 2016Sunuwar et al, , 2017aSunuwar et al, , 2017b. Another possibility is that luminal zinc may function as a regulator for intestinal microbiota and endosymbionts, or for the control of a commonly occurring natural pathogen (Brownlie et al, 2009;Bonfini et al, 2016;Mistry et al, 2016;Martino et al, 2017;Martinson et al, 2017;Clark and Walker, 2018).…”

Perturbed bone composition and integrity with disorganized osteoblast function in zinc receptor/Gpr39‐deficient mice

“…ZnR/Gpr39 was shown to play a regulatory role in sugar metabolism, neuronal transmission, and regulation of gut epithelia proliferation and absorption (30). Importantly, several studies showed that ZnR/Gpr39 ablation may result in perturbations of pancreatic endocrine functions, obesity, and gut permeability (47)(48)(49)(50)(51), and zinc itself or its transporters have also been associated with pancreatic function. Both proper glucose metabolism and an intact gut epithelial barrier are important for maintaining healthy bone homeostasis, especially under conditions of bone challenge, such as in the case of postmenopausal osteoporosis (52)(53)(54)(55)(56).…”

The zinc sensing receptor ZnR GPR39 in health and disease

“…Physiological relevance was further established when Zn 2+ release from Caco-2 colonocytes was sufficient to induce ZnR/GPR39-dependent cell growth and tight junction formation [69,89]. In addition, in a cholera toxin model of diarrhea or a dextran sodium sulfate model of colitis, ZnR/GPR39-dependent pathways were not activated following dietary Zn 2+ depletion [90,91]. Similarly, in the prostate, where there are high concentrations of Zn 2+ /citrate complex and transient release of this ion is likely to occur following cell death or changes in pH, ZnR/GPR39 is adapted to the relevant concentrations, which range from 10 to 200 µM [59].…”