Ca2+-sensing receptor (CaSR) belongs to family C of G protein-coupled receptors and is activated by the endogenous agonists such as Ca2+. Stimulation of CaSR expressed in vascular endothelial cells through the increase in extracellular Ca2+ concentration ([Ca2+]o) is reported to induce vasorelaxation via the production of nitric oxide (NO). The purpose of the present study is to characterize the CaSR-mediated NO production in human vascular endothelial cells. In human endothelial EA.hy926 cells, the increase in [Ca2+]o from 0.2 to 2 mM induced a concentration-dependent increase in intracellular Ca2+ concentration, which was significantly inhibited by NPS 2143 (a CaSR antagonist) and YM-254890 (a Gq/11 protein inhibitor). Stimulation with 2 mM Ca2+ for 4 h elicited an increase in the phosphorylation level of eNOS at Ser1177, which was significantly depressed by NPS 2143, YM-254890, and removal of Ca2+ from the medium. Ca2+ (2 mM) induced an increase in NO production, which was inhibited by NPS 2143, YM-254890, removal of Ca2+ from the medium, and L-NAME (a competitive eNOS inhibitor). These results provide evidence that activation of CaSR with extracellular Ca2+ facilitates NO release from human vascular endothelial cells via a Gq/11 protein-eNOS-dependent pathway.

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