No 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 calciumsensing 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.Parietal cells secrete gastric acid in response to stimulation by either neuronally derived acetylcholine or via a biphasic endocrine pathway. In the endocrine pathway, release of gastrin from antral G cells leads to the activation of histaminecontaining enterochromaffin-like (ECL) 1 cells (1). ECL cells then release histamine, which in turn initiates the direct insertion and activation of H ϩ ,K ϩ -ATPase into the apical membrane of parietal cells. The exposure to histamine also causes a simultaneous rise in intracellular Ca 2ϩ . Elevations in intracellular Ca 2ϩ during this period have been associated with increased acid secretion and, as a result, have been used as an additional marker of the secretory process (2-4). Recently, a direct correlation between activation of the divalent cation receptor and Ca 2ϩ entry into parietal cells has been established in which activation of the receptor by either divalent or trivalent ions leads to a rise in intracellular Ca 2ϩ both from intraand extracellular sites (5). Furthermore, the divalent receptor has been shown to modulate membrane Ca 2ϩ channels and intracellular Ca 2ϩ levels in G cells of the stomach (5). Recently, using calcium receptor-transfected human embryonic kidney cells, the first demonstration of calcium receptor modulation of a channel protein and an intracellular Ca 2ϩ pathway was made (6). After activation of parietal cells by histamine, acid secretion occurs and the luminal pH of the gland decreases to approximately pH 1, leading to t...