Sphingosine Kinase 1 Mediates Transmembrane Calcium Entry via Store‐Operated Calcium Channel

Abstract

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 intracellular rather than extracellular actions. Collectively, these data implicate SK1 as the missing link that connects the angiotensin AT1A receptor to transmembrane Ca2+ influx and identify SOC as a potential intracellular target for SK1/S1P axis.