| First Author | Sunuwar L | Year | 2017 |
| Journal | Biochim Biophys Acta | Volume | 1863 |
| Issue | 4 | Pages | 947-960 |
| PubMed ID | 28093242 | Mgi Jnum | J:255645 |
| Mgi Id | MGI:6104987 | Doi | 10.1016/j.bbadis.2017.01.009 |
| Citation | Sunuwar L, et al. (2017) The Zn(2+)-sensing receptor, ZnR/GPR39, upregulates colonocytic Cl(-) absorption, via basolateral KCC1, and reduces fluid loss. Biochim Biophys Acta 1863(4):947-960 |
| abstractText | 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 Zn(2+) 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 Zn(2+) we observed similar fluid accumulation in WT and ZnR/GPR39 KO mice, indicating that Zn(2+) and ZnR/GPR39 are both required for a beneficial effect of Zn(2+) 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 Zn(2+) 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. |
