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HORMONES AND SIGNALING

The calcium-sensing receptor acts as a modulator of gastric acid secretion in freshly isolated human gastric glands

¹Institute of Physiology and Center for Integrative Human Physiology and ²Division of Visceral and Transplant Surgery, University of Zurich, Zurich, Switzerland; and Departments of ³Cellular and Molecular Physiology and ⁴Surgery, Yale School of Medicine, New Haven, Connecticut

Submitted 29 December 2004 ; accepted in final form 12 August 2005

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 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 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 gastric H⁺-K⁺-ATPase and the CaSR. Functional experiments using the pH-sensitive dye 2',7'-bis-(2-carboxyethyl)-5-(and 6)-carboxyfluorescein and measurement of intracellular pH changes allowed us to estimate the activity of 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 the CaSR and reduced 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 conditions of low extracellular divalent cations. This stimulation was not due to release of histamine from neighbouring enterochromaffin-like 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 the CaSR by Gd³⁺ led to a sustained increase in intracellular Ca²⁺ even under conditions of low extracellular divalent cations. These experiments demonstrate the presence of a functional CaSR in the human stomach and show that this receptor may modulate the activity of 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.

stomach; H⁺-K⁺-ATPase; parietal cells

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