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Angiotensin II plays a critical role in the regulation of vascular tone and blood pressure mainly via regulation of Ca2+ mobilization. Several reports have implicated sphingosine kinase 1 (SK1)/sphingosine 1-phosphate (S1P) in the mobilization of intracellular Ca2+ through a yet undefined mechanism. Here we demonstrate that angiotensin II induces biphasic calcium entry in vascular smooth muscle cells, consisting of an immediate peak due to inositol tris-phosphate-dependent release of intracellular calcium, followed by a sustained transmembrane Ca2+ influx through store operated calcium channels (SOC). Inhibition of SK1 attenuates the second phase of transmembrane Ca2+ influx, suggesting a role for SK1 in angiotensin II-dependent activation of SOC. Intracellular S1P triggers SOC-dependent Ca2+ influx independent of S1P receptors, while external application of S1P stimulated S1P receptor-dependent Ca2+ influx that is insensitive to inhibitors of SOC, suggesting that the SK1/S1P axis regulates SOC entry via ...