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.

Single-Dose and Multiple-Dose Administration of Indole-3-Carbinol to Women: Pharmacokinetics Based on 3,3′-Diindolylmethane

“…The dose of I3C administered to mice (i.e., 250 mg/kg) is 10 to 40 times higher than the body weight -normalized doses administered to our human subjects, resulting in a proportional skewing of I3C gastric concentration. In regard to acidity, the gastric pH of rodents (25,26) is markedly higher than that of humans (27), resulting in a slower consumption of I3C and a different distribution of products than would be expected at the pH of the human stomach (20,23). All subjects for I3C pharmacokinetic studies had been fasting, ensuring a highly acidic gastric environment that would favor rapid consumption of I3C.…”

Taste Receptors in the Gastrointestinal Tract II.l-Amino acid sensing by calcium-sensing receptors: implications for GI physiology

“…6). In addition, it has been shown recently that the CaR-active amino acids, L-Phe and L-Trp, stimulate acid secretion from isolated gastric glands in a manner that is highly dependent on variations in the Ca 2ϩ o between 1.0 and 2.0 mM, behavior that is typical of the CaR (10). Although the system L-amino acid transporter may also contribute to amino acid-induced activation of gastric acid secretion (30), the specific inhibitor 2-amino-2-norbornanecarboxylic acid did not block these effects of L-Phe or L-Trp (10).…”

Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: A randomized, crossover, controlled clinical trial

“…fasting gastric pH values in healthy individuals are 1 to 3, and calcium is highly soluble in this environment. Because dietary protein is known to increase gastric acid secretion, (10)(11)(12) we decided to study the effect of a PPI in the setting of a highprotein diet, thereby maximizing gastric acid output. When acidic gastric chyme enters the duodenum, it stimulates secretin production, causing pancreatic and intestinal epithelial secretion of bicarbonate.…”

“…The study employed a crossover design in which each study subject served as his or her own control, thereby eliminating the confounding effect of interindividual variation on calcium absorption. We chose to use a high-protein diet for all interventions in our study because available data indicate that this would augment gastric acid production and intestinal calcium absorption, (10)(11)(12)(13) allowing us the best opportunity to quantify the contribution of gastric acid to calcium absorption.…”