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1 Department of Surgery, Yale University, School of Medicine, New Haven, CT, USA; University of Connecticut, School of Allied Health, Storrs, CT, USA
2 University of Connecticut, School of Allied Health, Storrs, CT, USA
3 Department of Surgery, Yale University, School of Medicine, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale University, School of Medicine, New Haven, CT, USA
4 Department of Medicine, Yale University, School of Medicine, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: john.geibel{at}yale.edu.
Parietal cells are the primary acid secretory cells of the stomach. We have previously shown that activation of the CaSR by divalent (Ca2+) or trivalent (Gd3+) ions stimulates acid production in the absence of secretagogues by increasing H+,K+-ATPase activity. When over-expressed in HEK-293 cells, the CaSR can be allosterically activated by Lamino acids in the presence of physiological concentrations of extracellular Ca2+ (Ca2+ o; 1.5-2.5 mM). To determine if the endogenously expressed parietal cell CaSR is allosterically activated by L-amino acids, we examined the effect of the amino acids Lphe, L-trp and L-leu 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 Ca2+ o in the absence of secretagogues caused a dose dependent increase in H+ extrusion. These effects were amplified by addition of amino acids at various Ca2+ o concentrations. Blocking the H2 receptor with cimetidine or inhibiting system L amino acid transport with BCH 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 Ca2+ o concentration, can induce acid secretion independent of hormonal stimulation via allosteric activation of the stomach CaSR.
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