H/dipeptide absorption across the human intestinal epithelium is controlled indirectly via a functional Na/H exchanger

Gastroenterology. 2002 May;122(5):1322-33. doi: 10.1053/gast.2002.32992.


Background & aims: For optimal nutrient absorption to occur, the enterocyte must express a range of specialist ion-driven carrier proteins that function cooperatively in a linked and mutually dependent fashion. Thus, absorption via the human intestinal H(+)-coupled di/tripeptide transporter (hPepT1) is dependent on maintenance of the trans-apical driving force (the H(+)-electrochemical gradient) established, in part, by brush-border Na(+)/H(+) exchanger (NHE3) activity. This study aimed to examine whether physiologic regulation of NHE3 activity can limit hPepT1 capacity and, therefore, protein absorption after a meal.

Methods: hPepT1 and NHE3 activities were determined in intact human intestinal epithelial Caco-2 cell monolayers by measurements of [(14)C]glycylsarcosine transport and uptake, (22)Na(+)-influx, H(+)-influx, and H(+)-efflux. Expression of NHE regulatory factors was determined by reverse-transcriptase polymerase chain reaction.

Results: Optimal dipeptide transport was observed in the presence of a transapical pH gradient and extracellular Na(+). At apical pH 6.5, and only in Na(+)-containing media, protein kinase A activation (by forskolin or vasoactive intestinal peptide) or selective NHE3 inhibition (by S1611) reduced transepithelial dipeptide transport and cellular accumulation by a reduction in the capacity (without effect on affinity) of dipeptide uptake.

Conclusions: Protein kinase A-mediated modulation of intestinal dipeptide absorption is indirect via effects on the apical Na(+)/H(+) exchanger.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biological Transport
  • Caco-2 Cells
  • Carrier Proteins / physiology*
  • Colforsin / pharmacology
  • Cyclic AMP / physiology
  • Cyclic AMP-Dependent Protein Kinases / physiology
  • Dipeptides / metabolism*
  • Humans
  • Hydrogen-Ion Concentration
  • Intestinal Absorption*
  • Intestinal Mucosa / metabolism
  • Peptide Transporter 1
  • Phosphoproteins / genetics
  • RNA, Messenger / analysis
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers / physiology*
  • Symporters*
  • Vasoactive Intestinal Peptide / metabolism


  • Carrier Proteins
  • Dipeptides
  • Peptide Transporter 1
  • Phosphoproteins
  • RNA, Messenger
  • SLC15A1 protein, human
  • SLC9A3 protein, human
  • Sodium-Hydrogen Exchanger 3
  • Sodium-Hydrogen Exchangers
  • Symporters
  • growth factor-activatable Na-H exchanger NHE-1
  • sodium-hydrogen exchanger regulatory factor
  • Colforsin
  • Vasoactive Intestinal Peptide
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases