Stimulation of gastric acid secretion from parietal cells occurs after stimulation of a variety of neurotransmitter or hormone receptors such as acetyl choline or histamine receptors, but also by the Ca2+-sensing receptor (CaSR) located at the basolateral membrane of the acid-secretory gastric parietal cell. We investigated if the CaSR is functionally expressed in freshly isolated gastric glands from human patients, if the CaSR is influencing the histamine induced activation of H⁺/K⁺- ATPase activity, and which signal cascade mediates these effects. Immunohistochemistry demonstrated the expression of the CaSR in parietal cells. Intracellular pH-measurements detected the activity of the histamine stimulated and omeprazole inhibitable H⁺/K⁺-ATPase in single parietal cells. The activity of the H⁺/K⁺ATPase was increased by Gd³⁺, a potent activator of CaSR. Inhibition of small G-proteins (Gi and Go) with pertussis toxin, as well as inhibition of PLC (with U73122) did not completely prevented the stimulatory effect of Gd³⁺. Our data suggest 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- activity and that Ca²⁺-dependent and independent PKC-isozymes are part of the signalling cascade of the CaSR.