L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells

Am J Physiol Gastrointest Liver Physiol. 2005 Oct;289(4):G664-9. doi: 10.1152/ajpgi.00096.2005. Epub 2005 Jun 16.


Parietal cells are the primary acid secretory cells of the stomach. We have previously shown that activation of the calcium-sensing receptor (CaSR) by divalent (Ca(2+)) or trivalent (Gd(3+)) ions stimulates acid production in the absence of secretagogues by increasing H(+),K(+)-ATPase activity. When overexpressed in HEK-293 cells, the CaSR can be allosterically activated by L-amino acids in the presence of physiological concentrations of extracellular Ca(2+) (Ca(o)(2+); 1.5-2.5 mM). To determine whether the endogenously expressed parietal cell CaSR is allosterically activated by L-amino acids, we examined the effect of the amino acids L-phenylalanine (L-Phe), L-tryptophan, and L-leucine on acid secretion. In ex vivo whole stomach preparations, exposure to L-Phe resulted in gastric luminal pH significantly lower than controls. Studies using D-Phe (inactive isomer) failed to elicit a response on gastric pH. H(+)-K(+)-ATPase activity was monitored by measuring the intracellular pH (pH(i)) of individual parietal cells in isolated rat gastric glands and calculating the rate of H(+) extrusion. We demonstrated that increasing Ca(o)(2+) in the absence of secretagogues caused a dose-dependent increase in H(+) extrusion. These effects were amplified by the addition of amino acids at various Ca(o)(2+) concentrations. Blocking the histamine-2 receptor with cimetidine or inhibiting system L-amino acid transport with 2-amino-2-norbornane-carboxylic acid did not affect the rate of H(+) extrusion in the presence of L-Phe. These data support the conclusion that amino acids, in conjunction with a physiological Ca(o)(2+) concentration, can induce acid secretion independent of hormonal stimulation via allosteric activation of the stomach CaSR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acids / pharmacology*
  • Animals
  • Anti-Ulcer Agents / pharmacology
  • Cimetidine / pharmacology
  • Dose-Response Relationship, Drug
  • Gastric Acid / metabolism*
  • Gastric Acidity Determination
  • H(+)-K(+)-Exchanging ATPase / metabolism
  • Male
  • Mice
  • Omeprazole / pharmacology
  • Parietal Cells, Gastric / drug effects
  • Parietal Cells, Gastric / enzymology
  • Parietal Cells, Gastric / metabolism*
  • Phenylalanine / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Calcium-Sensing / agonists*
  • Stimulation, Chemical
  • Tryptophan / pharmacology


  • Amino Acids
  • Anti-Ulcer Agents
  • Receptors, Calcium-Sensing
  • Phenylalanine
  • Cimetidine
  • Tryptophan
  • H(+)-K(+)-Exchanging ATPase
  • Omeprazole