Background & Aims Oral rehydration solutions reduce diarrhea-associated mortality. Stimulated sodium absorption by these solutions is mediated by the Na+/H+hydrogen exchanger NHE3 and is increased by Na+-glucose co-transport in vitro, but the mechanisms of this up-regulated process are only partially understood. Methods Intracellular pH was measured in jejunal enterocytes of wild-type mice and mice with disrupted Na+/H+ exchange regulatory co-factor 2 (NHERF2-/- mice) by multiphoton microscopy. Diarrhea was induced by cholera toxin. Caco-2BBe cells that express NHE3 and the sodium/glucose cotransporter 1 (SGLT1) were studied by fluorometry, before and after siRNA-mediated knockdown of NHERF1 or NHERF2. NHE3 distribution was assessed by cell-surface biotinylation and confocal microscopy. Brush-border mobility was determined by fluorescence recovery after photobleaching and confocal microscopy. Results The nonmetabolized SGLT1 substrate α-methyl-D-Glu (α-MD-G) activated jejunal NHE3; this process required Akt and NHERF2. α-MD-G normalized NHE3 activity after cholera toxininduced diarrhea. α-MD-Gstimulated jejunal NHE3 activity was defective in NHERF2-/- mice and cells with NHERF2 knockdown, but occurred normally with NHERF1 knockdown; was associated with increased NHE3 surface expression in Caco-2 cells, which also was NHERF2-dependent; was associated with dissociation of NHE3 from NHERF2 and an increase in the NHE3 mobile fraction from the brush border; and was accompanied by a NHERF2 ezrin-radixin- moesinbinding domain-dependent increase in co-precipitation of ezrin with NHE3. Conclusions SGLT1-mediated Na-glucose co-transport stimulates NHE3 activity in vivo by an Akt- and NHERF2-dependent signaling pathway. It is associated with increased brush-border NHE3 and association between ezrin and NHE3. Activation of NHE3 corrects cholera toxininduced defects in Na absorption and might contribute to the efficacy of oral rehydration solutions.

Additional Metadata
Keywords Cholera Toxin, Exocytosis, Ezrin, Intestinal Na Absorption, NHERF2
Persistent URL dx.doi.org/10.1053/j.gastro.2010.10.042, hdl.handle.net/1765/31629
Citation
Lin, R., Murtazina, R., Cha, B., Chakraborty, M., Sarker, R., Chen, T., … Donowitz, M.. (2011). D-glucose acts via sodium/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+/H+ exchange regulatory factor 2dependent process. Gastroenterology, 140(2), 560–571. doi:10.1053/j.gastro.2010.10.042