H(+)/solute-induced intracellular acidification leads to selective activation of apical Na(+)/H(+) exchange in human intestinal epithelial cells

J Clin Invest. 1999 Sep;104(5):629-35. doi: 10.1172/JCI7192.


The intestinal absorption of many nutrients and drug molecules is mediated by ion-driven transport mechanisms in the intestinal enterocyte plasma membrane. Clearly, the establishment and maintenance of the driving forces - transepithelial ion gradients - are vital for maximum nutrient absorption. The purpose of this study was to determine the nature of intracellular pH (pH(i)) regulation in response to H(+)-coupled transport at the apical membrane of human intestinal epithelial Caco-2 cells. Using isoform-specific primers, mRNA transcripts of the Na(+)/H(+) exchangers NHE1, NHE2, and NHE3 were detected by RT-PCR, and identities were confirmed by sequencing. The functional profile of Na(+)/H(+) exchange was determined by a combination of pH(i), (22)Na(+) influx, and EIPA inhibition experiments. Functional NHE1 and NHE3 activities were identified at the basolateral and apical membranes, respectively. H(+)/solute-induced acidification (using glycylsarcosine or beta-alanine) led to Na(+)-dependent, EIPA-inhibitable pH(i) recovery or EIPA-inhibitable (22)Na(+) influx at the apical membrane only. Selective activation of apical (but not basolateral) Na(+)/H(+) exchange by H(+)/solute cotransport demonstrates that coordinated activity of H(+)/solute symport with apical Na(+)/H(+) exchange optimizes the efficient absorption of nutrients and Na(+), while maintaining pH(i) and the ion gradients involved in driving transport.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / pathology
  • Cell Polarity
  • Colonic Neoplasms / pathology
  • Epithelial Cells / metabolism
  • Gastrointestinal Contents
  • Humans
  • Hydrogen-Ion Concentration
  • Intestinal Mucosa / metabolism*
  • Ion Transport
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Protein Isoforms / biosynthesis*
  • Protein Isoforms / genetics
  • Protons*
  • RNA, Messenger / biosynthesis
  • RNA, Neoplasm / biosynthesis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium / metabolism*
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / biosynthesis*
  • Sodium-Hydrogen Exchangers / genetics
  • Tumor Cells, Cultured


  • Neoplasm Proteins
  • Protein Isoforms
  • Protons
  • RNA, Messenger
  • RNA, Neoplasm
  • SLC9A2 protein, human
  • SLC9A3 protein, human
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • growth factor-activatable Na-H exchanger NHE-1
  • Sodium