Published online before print May 4, 2006, doi: 10.1161/01.RES.0000225284.36490.a2
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Submitted on July 5, 2005
Revised on March 23, 2006
Accepted on April 20, 2006
A Sphingosine-1-Phosphate-Activated Calcium Channel Controlling Vascular Smooth Muscle Cell Motility
Shang-Zhong Xu ;
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.
* To whom correspondence should be addressed. 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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