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Vol. 19, Issue 8, 3203-3211, August 2008

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Elucidation of a TRPC6-TRPC5 Channel Cascade That Restricts Endothelial Cell Movement

Pinaki Chaudhuri^*, Scott M. Colles^*, Manjunatha Bhat, David R. Van Wagoner, Lutz Birnbaumer, and Linda M. Graham^*,||

*Department of Biomedical Engineering, Center for Anesthesiology Research, Department of Molecular Cardiology, and ^||Department of Vascular Surgery, Cleveland Clinic, Cleveland, OH 44195; and National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709

Submitted August 8, 2007; Revised April 23, 2008; Accepted May 8, 2008
Monitoring Editor: John York

Canonical transient receptor potential (TRPC) channels are opened by classical signal transduction events initiated by receptor activation or depletion of intracellular calcium stores. Here, we report a novel mechanism for opening TRPC channels in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation. When endothelial cells (ECs) are incubated in lysophosphatidylcholine (lysoPC), rapid translocation of TRPC6 initiates calcium influx that results in externalization of TRPC5. Activation of this TRPC6–5 cascade causes a prolonged increase in intracellular calcium concentration ([Ca²⁺]_i) that inhibits EC movement. When TRPC5 is down-regulated with siRNA, the lysoPC-induced rise in [Ca²⁺]_i is shortened and the inhibition of EC migration is lessened. When TRPC6 is down-regulated or EC from TRPC6^–/– mice are studied, lysoPC has minimal effect on [Ca²⁺]_i and EC migration. In addition, TRPC5 is not externalized in response to lysoPC, supporting the dependence of TRPC5 translocation on the opening of TRPC6 channels. Activation of this novel TRPC channel cascade by lysoPC, resulting in the inhibition of EC migration, could adversely impact on EC healing in atherosclerotic arteries where lysoPC is abundant.

Address correspondence to: Linda M. Graham (grahamL{at}ccf.org)

Abbreviations used: AS, antisense oligonucleotide; [Ca²⁺]_i, intracellular calcium concentration; ECs, endothelial cells; lysoPC, lysophosphatidylcholine; MAECs, mouse aortic ECs; Scr, scrambled oligonucleotide; TRP, transient receptor potential (protein); TRPC, canonical transient receptor potential (protein); TRPC6^–/–, TRPC6 deficient.

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