title: L-type amino acids stimulate gastric acid secretion by activation of the calcium-sensing receptor in parietal cells.
abstract: 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.
authors.affiliation: Dept. of Surgery, Yale University, New Haven, CT 06520, USA.
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Busque
authors.forename: Jane E
authors.initials: JE
authors.lastname: Kerstetter
authors.forename: John P
authors.initials: JP
authors.lastname: Geibel
authors.forename: Karl
authors.initials: K
authors.lastname: Insogna
mesh_terms: D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D002927:Cimetidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D017506:H(+)-K(+)-Exchanging ATPase / Q000378:metabolism; D008297:Male; D051379:Mice; D009853:Omeprazole / Q000494:pharmacology; D010295:Parietal Cells, Gastric / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010649:Phenylalanine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000819:agonists*; D013268:Stimulation, Chemical; D014364:Tryptophan / Q000494:pharmacology
chemical_list: D000596:Amino Acids; D000897:Anti-Ulcer Agents; D044169:Receptors, Calcium-Sensing; D010649:Phenylalanine; D002927:Cimetidine; D014364:Tryptophan; D017506:H(+)-K(+)-Exchanging ATPase; D009853:Omeprazole