NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia |
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Authors: | Turner J R Black E D |
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Institution: | Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan 48201, USA. jturner@bsd.uchicago.edu |
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Abstract: | Cytoplasmic pH (pHi) was evaluated duringNa+-glucose cotransport in Caco-2 intestinal epithelialcell monolayers. The pHi increased by 0.069 ± 0.002 within 150 s after initiation of Na+-glucosecotransport. This increase occurred in parallel with glucose uptake andrequired expression of the intestinal Na+-glucosecotransporter SGLT1. S-3226, a preferential inhibitor ofNa+/H+ exchanger (NHE) isoform 3 (NHE3),prevented cytoplasmic alkalinization after initiation ofNa+-glucose cotransport with an ED50 of 0.35 µM, consistent with inhibition of NHE3, but not NHE1 or NHE2. Incontrast, HOE-694, a poor NHE3 inhibitor, failed to significantlyinhibit pHi increases at <500 µM.Na+-glucose cotransport was also associated with activationof p38 mitogen-activated protein (MAP) kinase, and the p38 MAP kinase inhibitors PD-169316 and SB-202190 prevented pHi increasesby 100 ± 0.1 and 86 ± 0.1%, respectively. Conversely,activation of p38 MAP kinase with anisomycin induced NHE3-dependentcytoplasmic alkalinization in the absence of Na+-glucosecotransport. These data show that NHE3-dependent cytoplasmic alkalinization occurs after initiation of SGLT1-mediatedNa+-glucose cotransport and that the mechanism of this NHE3activation requires p38 MAP kinase activity. This coordinatedregulation of glucose (SGLT1) and Na+ (NHE3) absorptiveprocesses may represent a functional activation of absorptiveenterocytes by luminal nutrients. |
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