NHE3-dependent cytoplasmic alkalinization is triggered by Na(+)-glucose cotransport in intestinal epithelia

Am J Physiol Cell Physiol. 2001 Nov;281(5):C1533-41. doi: 10.1152/ajpcell.2001.281.5.C1533.


Cytoplasmic pH (pH(i)) was evaluated during Na(+)-glucose cotransport in Caco-2 intestinal epithelial cell monolayers. The pH(i) increased by 0.069 +/- 0.002 within 150 s after initiation of Na(+)-glucose cotransport. This increase occurred in parallel with glucose uptake and required expression of the intestinal Na(+)-glucose cotransporter SGLT1. S-3226, a preferential inhibitor of Na(+)/H(+) exchanger (NHE) isoform 3 (NHE3), prevented cytoplasmic alkalinization after initiation of Na(+)-glucose cotransport with an ED(50) of 0.35 microM, consistent with inhibition of NHE3, but not NHE1 or NHE2. In contrast, HOE-694, a poor NHE3 inhibitor, failed to significantly inhibit pH(i) increases at <500 microM. Na(+)-glucose cotransport was also associated with activation of p38 mitogen-activated protein (MAP) kinase, and the p38 MAP kinase inhibitors PD-169316 and SB-202190 prevented pH(i) increases by 100 +/- 0.1 and 86 +/- 0.1%, respectively. Conversely, activation of p38 MAP kinase with anisomycin induced NHE3-dependent cytoplasmic alkalinization in the absence of Na(+)-glucose cotransport. These data show that NHE3-dependent cytoplasmic alkalinization occurs after initiation of SGLT1-mediated Na(+)-glucose cotransport and that the mechanism of this NHE3 activation requires p38 MAP kinase activity. This coordinated regulation of glucose (SGLT1) and Na(+) (NHE3) absorptive processes may represent a functional activation of absorptive enterocytes by luminal nutrients.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Actomyosin / metabolism
  • Blotting, Western
  • Caco-2 Cells
  • Cytoplasm / drug effects
  • Cytoplasm / enzymology*
  • Enzyme Inhibitors / pharmacology
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism
  • Epithelium / drug effects
  • Epithelium / metabolism
  • Humans
  • Hydrogen-Ion Concentration
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism*
  • Membrane Glycoproteins / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Monosaccharide Transport Proteins / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Sodium-Glucose Transporter 1
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / metabolism*
  • p38 Mitogen-Activated Protein Kinases


  • Enzyme Inhibitors
  • Membrane Glycoproteins
  • Monosaccharide Transport Proteins
  • SLC5A1 protein, human
  • SLC9A3 protein, human
  • Sodium-Glucose Transporter 1
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Actomyosin
  • Phosphatidylinositol 3-Kinases
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases