Abstract
Divalent cation receptors have recently been identified in a wide variety of tissues and organs, yet their exact function remains controversial. We have previously identified a member of this receptor family in the stomach and have demonstrated that it is localized to the parietal cell, the acid secretory cell of the gastric gland. The activation of acid secretion has been classically defined as being regulated by two pathways: a neuronal pathway (mediated by acetylcholine) and an endocrine pathway (mediated by gastrin and histamine). Here, we identified a novel pathway modulating gastric acid secretion through the stomach calcium-sensing receptor (SCAR) located on the basolateral membrane of gastric parietal cells. Activation of SCAR in the intact rat gastric gland by divalent cations (Ca(2+) or Mg(2+)) or by the potent stimulator gadolinium (Gd(3+)) led to an increase in the rate of acid secretion through the apical H+,K+ -ATPase. Gd(3+) was able to activate acid secretion through the omeprazole-sensitive H+,K+ -ATPase even in the absence of the classical stimulator histamine. In contrast, inhibition of SCAR by reduction of extracellular cations abolished the stimulatory effect of histamine on gastric acid secretion, providing evidence for the regulation of the proton secretory transport protein by the receptor. These studies present the first example of a member of the divalent cation receptors modulating a plasma membrane transport protein and may lead to new insights into the regulation of gastric acid secretion.
Highlights
Parietal cells secrete gastric acid in response to stimulation by either neuronally derived acetylcholine or via a biphasic endocrine pathway
We used several experimental approaches to test the decisive role of stomach calciumsensing receptor (SCAR) in gastric acid secretion
This receptor may modulate the conventional stimulatory hormonal pathways inasmuch as activation or inhibition of SCAR resulted in either an immediate activation or cessation of acid secretion, respectively. These studies suggest a possible mechanism for the tight regulation of pHi of the parietal cell, a feature that has not been clearly defined in the classical model of acid secretion
Summary
Parietal cells secrete gastric acid in response to stimulation by either neuronally derived acetylcholine or via a biphasic endocrine pathway. After activation of parietal cells by histamine, acid secretion occurs and the luminal pH of the gland decreases to approximately pH 1, leading to the efflux of protons from the gland lumen and resulting in a subsequent decrease in intragastric pH. During this massive flux of protons the intracellular pH of parietal cells remains stable at approximately pH 7 [3, 7]. We demonstrate that SCAR modulates acid secretion via regulation of the Hϩ,Kϩ-ATPase This regulation of the transport protein appears to be independent of vesicular trafficking and the conventional hormonal pathways of acid secretion. Our studies present evidence for the first regulation of a membrane transport protein via a divalent cation receptor
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