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(Circulation Research. 2006;98:1381.)
© 2006 American Heart Association, Inc.

Cellular Biology

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

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

From the Institute of Membrane and Systems Biology (S.-Z.X., F.Z., J.L., P.S., A.M.D., P.K.F., D.M., J.N., A.C., A.N.B., D.J.B.), University of Leeds, United Kingdom; Cellular Pharmacology (K.M.), School of Pharmacy, Aichi Gakuin University, Nagoya, Japan; School of Medicine (K.E.P.), University of Leeds, United Kingdom; and Yorkshire Heart Centre (S.S., C.M.M.), General Infirmary at Leeds, United Kingdom.

Correspondence to Professor D.J. Beech, Institute of Membrane and Systems Biology, University of Leeds, Leeds, LS2 9JT, UK. E-mail d.j.beech{at}leeds.ac.uk

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.

Key Words: vascular smooth muscle • vein • sphingosine-1–phosphate • transient receptor potential • calcium channel

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