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1 Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Division of Visceral and Transplant Surgery, University of Zurich, Zurich, Switzerland
2 Division of Visceral and Transplant Surgery, University of Zurich, Zurich, Switzerland
3 Institute of Physiology and Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
4 Department of Cellular and Molecular Physiology, Yale Medical School, New Haven, CT, USA
5 Department of Cellular and Molecular Physiology, Yale Medical School, New Haven, CT, USA; Department of Surgery, Yale Medical School, New Haven, CT, USA
* To whom correspondence should be addressed. E-mail: Wagnerca{at}access.unizh.ch.
Gastric acid secretion is activated by two distinct pathways, a neuronal pathway via the vagus nerve and release of acetylcholine, and an endocrine pathway involving gastrin and histamine. Recently, we have demonstrated that activation of H+/K+-ATPase activity in parietal cells in freshly isolated rat gastric glands is modulated by the calcium sensing receptor (CaSR). Here we investigated if the CaSR is functionally expressed in freshly isolated gastric glands from human patients undergoing surgery and if the CaSR is influencing the histamine induced activation of H+/K+-ATPase activity. In tissue samples obtained from patients, immunohistochemistry demonstrated the expression in parietal cells of both subunits of the gastric H+/K+-ATPase and the CaSR. Functional experiments using the pH-sensitive dye BCECF and measuring intracellular pH changes allowed estimation of the activity of the H+/K+-ATPase in single freshly isolated human gastric glands. Under control conditions, H+/K+-ATPase activity was stimulated by histamine (100 µM) and inhibited by omeprazole (100 µM). Reduction of the extracellular divalent cation concentration (0 Mg2+, 100 µM Ca2+) inactivated CaSR and reduced the histamine induced activation of H+/K+- ATPase activity. In contrast, activation of the CaSR with the trivalent cation Gd3+ caused activation of omeprazole-sensitive H+/K+-ATPase activity even in the absence of histamine and under low extracellular divalent cations. This stimulation was not due to release of histamine from neighbouring ECL cells as the stimulation persisted in the presence of the H2-receptor antagonist cimetidine (100 µM). Furthermore, intracellular calcium measurements with FURA-2 and Fluo-4 showed that activation of CaSR by Gd3+ led to a sustained increase in intracellular Ca2+ even under low extracellular divalent cations. These experiments demonstrate the presence of a functional calcium-sensing receptor in the human stomach and show that this receptor may modulate the activity of the acid-secreting H+/K+-ATPase in parietal cells. Furthermore, our results show the viability of freshly isolated human gastric glands and may allow the use of this preparation for experiments investigating the physiological regulation and properties of human gastric glands in vitro.
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