Modulations in extracellular calcium lead to H+-atpase-dependent acid secretion: A clarification of PPI failure

Kitay AM, Schneebacher MT, Schmitt A, Heschl K, Kopic S, Alfadda T, Alsaihati A, Link A, Geibel JP (2018)

Publication Type: Journal article

Publication year: 2018

Journal

American Journal of Physiology-Gastrointestinal and Liver Physiology American Physiological Society

Book Volume: 315

Pages Range: G36-G42

Journal Issue: 1

DOI: 10.1152/ajpgi.00132.2017

Abstract

The H+,K+-ATPase was identified as the primary proton secretory pathway in the gastric parietal cell and is the pharmacological target of agents suppressing acid secretion. Recently, we identified a second acid secretory protein expressed in the parietal cell, the vacuolar H+-ATPase (V-type ATPase). The aim of the present study was to further characterize H+-ATPase activation by modulations in extracellular calcium via the calcium sensing receptor (CaSR). Isolated gastric glands were loaded with the pH indicator dye BCECF-AM [2′,7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester] to measure intracellular pH. Experiments were conducted in the absence of sodium and potassium to monitor H+-ATPase-specific transport activity. CaSR was activated with the calcimimetic R568 (400 nM) and/or by modulations in extracellular Ca2+. Elevation in calcium concentrations increased proton extrusion from the gastric parietal cell. Allosteric modification of the CaSR via R568 and calcium increased vacuolar H+-ATPase activity significantly (ΔpH/minlowCa 2+ (0.1mM) = 0.001 ± 0.001, ΔpH/min normalCa 2+ (1.0mM) = 0.033 ± 0.004, ΔpH/minhighCa 2+ (5.0mM)=0.051 ± 0.005). Carbachol significantly suppressed calcium-induced gastric acid secretion via the H_-ATPase under sodium- and potassium-free conditions. We conclude that the V-type H_-ATPase is tightly linked to CaSR activation. We observed that proton pump inhibitor (PPI) exposure does not modulate H+-ATPase activity. This elevated blood calcium activation of the H+-ATPase could provide an explanation for recurrent reflux symptoms while taking a PPI therapy. NEW & NOTEWORTHY This study emphasizes the role of the H+-ATPase in acid secretion. We further demonstrate the modification of this proton excretion pathway by extracellular calcium and the activation of the calcium sensing receptor CaSR. The novelty of this paper is based on the modulation of the H+-ATPase via both extracellular Ca (activation) and the classical secretagogues histamine and carbachol (inactivation). Both activation and inactivation of this proton pump are independent of PPI modulation.

Involved external institutions

Yale University US United States (USA) (US) Otto-von-Guericke-Universität Magdeburg DE Germany (DE)

How to cite

APA:

Kitay, A.M., Schneebacher, M.T., Schmitt, A., Heschl, K., Kopic, S., Alfadda, T.,... Geibel, J.P. (2018). Modulations in extracellular calcium lead to H+-atpase-dependent acid secretion: A clarification of PPI failure. American Journal of Physiology-Gastrointestinal and Liver Physiology, 315(1), G36-G42. https://doi.org/10.1152/ajpgi.00132.2017

MLA:

Kitay, Alice Miriam, et al. "Modulations in extracellular calcium lead to H+-atpase-dependent acid secretion: A clarification of PPI failure." American Journal of Physiology-Gastrointestinal and Liver Physiology 315.1 (2018): G36-G42.

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