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A Sphingosine-1–Phosphate-Activated Calcium Channel Controlling Vascular Smooth Muscle Cell Motility

2006; Lippincott Williams & Wilkins; Volume: 98; Issue: 11 Linguagem: Inglês

10.1161/01.res.0000225284.36490.a2

1524-4571

Shang‐Zhong Xu, Katsuhiko Muraki, Fanning Zeng, Jing Li, Piruthivi Sukumar, Samir S. Shah, Alexandra Dedman, Philippa K. Flemming, Damian McHugh, Jacqueline Naylor, Alex Cheong, Alan N. Bateson, Christopher Munsch, Karen E. Porter, David J. Beech,

Ion channel regulation and function

In a screen of potential lipid regulators of transient receptor potential (TRP) channels, we identified sphingosine-1-phosphate (S1P) as an activator of TRPC5. We explored the relevance to vascular biology because S1P is a key cardiovascular signaling molecule. TRPC5 is expressed in smooth muscle cells of human vein along with TRPC1, which forms a complex with TRPC5. Importantly, S1P also activates the TRPC5-TRPC1 heteromultimeric channel. Because TRPC channels are linked to neuronal growth cone extension, we considered a related concept for smooth muscle. We find S1P stimulates smooth muscle cell motility, and that this is inhibited by E3-targeted anti-TRPC5 antibody. Ion permeation involving TRPC5 is crucial because S1P-evoked motility is also suppressed by the channel blocker 2-aminoethoxydiphenyl borate or a TRPC5 ion-pore mutant. S1P acts on TRPC5 via two mechanisms, one extracellular and one intracellular, consistent with its bipolar signaling functions. The extracellular effect appears to have a primary role in S1P-evoked cell motility. The data suggest S1P sensing by TRPC5 calcium channel is a mechanism contributing to vascular smooth muscle adaptation.