Gastric acid secretion is not only stimulated via the classical known neuronal and hormonal pathways but also by the Ca2+-Sensing Receptor (CaSR) located at the basolateral membrane of the acid-secretory gastric parietal cell. Stimulation of CaSR with divalent cations or the potent agonist Gd3+ leads to activation of the H+/K+-ATPase and subsequently to gastric acid secretion. Here we investigated the intracellular mechanism(s) mediating the effects of the CaSR on H+/K+-ATPase activity in freshly isolated human gastric glands. Inhibition of heterotrimeric G-proteins (Gi and Go) with pertussis toxin during stimulation of the CaSR with Gd3+ only partly reduced the observed stimulatory effect. A similar effect was observed with the PLC inhibitor U73122. The reduction of the H+/K+-ATPase activity measured after incubation of gastric glands with BAPTA-AM, a chelator of intracellular Ca2+, showed that intracellular Ca2+ plays an important role in the signalling cascade. TMB-8, a ER Ca2+store release inhibitor, prevented the stimulation of H+/K+-ATPase activity. Also verapamil, an inhibitor of L-type Ca2+-channels reduced stimulation suggesting that both the release of intracellular Ca2+ from the ER as well as Ca2+ influx into the cell are involved in CaSR-mediated H+/K+-ATPase activation. Chelerythrine, a general inhibitor of protein kinase C, and Gö 6976 which selectively inhibits Ca2+-dependent PKCα and PKCβI-isozymes completely abolished the stimulatory effect of Gd3+. In contrast, Ro 31-8220, a selective inhibitor of the Ca2+-independent PKCε and PKC-δ isoforms reduced the stimulatory effect of Gd3+ only about 60 %. On the other hand, activation of PKC with DOG led to an activation of H+/K+-ATPase activity which was only about 60 % of the effect observed with Gd3+. Incubation of the parietal cells with PD 098059 to inhibit ERK1/2 MAP-kinases showed a significant reduction of the Gd3+ effect. Thus, in the human gastric parietal cell the CaSR is coupled to pertussis toxin sensitive heterotrimeric G-Proteins and requires calcium to enhance the activity of the proton-pump. PLC, ERK 1/2 MAP-kinases as well as Ca2+ dependent and Ca2+-independent PKC isoforms are part of the down-stream signalling cascade.

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© 2007 S. Karger AG, Basel
2007
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