A sphingosine-1-phosphate-activated calcium channel controlling vascular smooth muscle cell motility.
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.
Xu
Shang-Zhong
SZ
Institute of Membrane and Systems Biology, University of Leeds, Leeds, LS2 9JT, UK.
Muraki
Katsuhiko
K
Zeng
Fanning
F
Li
Jing
J
Sukumar
Piruthivi
P
Shah
Samir
S
Dedman
Alexandra M
AM
Flemming
Philippa K
PK
McHugh
Damian
D
Naylor
Jacqueline
J
Cheong
Alex
A
Bateson
Alan N
AN
Munsch
Christopher M
CM
Porter
Karen E
KE
Beech
David J
DJ