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MUCOSAL BIOLOGY
Departments of 1Surgery, 2Cellular and Molecular Physiology, and 3Medicine, School of Medicine, Yale University, New Haven; and 4School of Allied Health, University of Connecticut, Storrs, Connecticut
Submitted 3 March 2005 ; accepted in final form 10 June 2005
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 (Ca2+) or trivalent (Gd3+) 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 Ca2+ (Cao2+; 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 (pHi) of individual parietal cells in isolated rat gastric glands and calculating the rate of H+ extrusion. We demonstrated that increasing Cao2+ 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 Cao2+ 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 Cao2+ concentration, can induce acid secretion independent of hormonal stimulation via allosteric activation of the stomach CaSR.
stomach; pH; H-K-ATPase; rat; mouse; gastric glands
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