The relation between gastrointestinal organs and bone metabolism has become clearer during the last decades. Of paramount importance is the tight and intertwined regulation of gastric acid secretion and bone metabolism in regard of diseases caused by dysfunction of any of these or intermediary organs or mediators. The importance of the functions of the endocrine modulators 1,25(OH) vitamin D (calcitriol), PTH, and calcitonin becomes clear when seeing misbalances and its impact on the skeleton. Another important player in the gut-bone signaling axis is calcium, which is operating through the calcium-sensing receptor (CaSR). The CaSR is located on diverse tissues of the human body, such as the parathyroid glands, stomach, intestine, and kidney. The strict regulation of calcium homeostasis is of high importance and any disturbances have immense consequences for the body. Mechanisms and therapeutic implications, as well as diseases caused by imbalances on the stomach-bone signaling axis, are highlighted in the following chapter.

Background/Aims: L-arginine is an important mediator of cell division, wound healing, and immune function. It can be transformed by the nitric oxide synthase (NOS) to nitric oxide (NO), an important cell signaling molecule. Recent studies from our laboratory demonstrate specific effects of L-arginine (10mM) exposure on gastric acid secretion in rat parietal cells. Methods: Studies were performed with isolated gastric glands and the pH sensitive dye BCECF-AM +/- L-arginine to examine its effects on acid secretion. The direct NO-donor diethylamine NONOate sodium salt hydrate, was also used while monitoring intracellular pH. The specific inhibitor of the intracellular NO signal cascade ODQ was also used. Results: We found that gastric proton extrusion was activated with application of L-arginine (10mM), in a separate series when L-arginine (10mM) + L-NAME (30µM) were added there was no acid secretion. Addition of the NO-donor diethylamine NONOate sodium salt hydrate (10µM) also induced acid secretion. When the selective sGC-inhibitor ODQ was added with NONOate we did not observe acid secretion. Conclusion: We conclude that L-arginine is a novel secretagogue, which can mediate gastric acid secretion. Furthermore, the intake of L-arginine causes direct activation of the H⁺, K⁺ ATPase and increased proton extrusion from parietal cells resulting in the increased risk for acid-related diseases. The NO/sGC/cGMP pathway has never been described as a possible intracellular mechanism for H⁺, K⁺ ATPase activation before and presents a completely new scientific finding. Moreover, our studies demonstrate a novel role for L-NAME to effectively eliminate NOS induced acid secretion and thereby reducing the risk for L-arginine inducible ulcer disease.

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 Ca. 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/min = 0.001 ± 0.001, ΔpH/min = 0.033 ± 0.004, ΔpH/min = 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.