Functional role of vanilloid transient receptor potential 4-canonical transient receptor potential 1 complex in flow-induced Ca2+ influx

Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):851-8. doi: 10.1161/ATVBAHA.109.196584. Epub 2010 Jan 21.


Objective: The present study is aimed at investigating the interaction of TRPV4 with TRPC1 and the functional role of such an interaction in flow-induced Ca(2+) influx. Hemodynamic blood flow is an important physiological factor that modulates vascular tone. One critical early event in this process is a cytosolic Ca(2+) ([Ca(2+)](i)) rise in endothelial cells in response to flow.

Methods and results: With the use of fluorescence resonance energy transfer, coimmunoprecipitation, and subcellular colocalization methods, it was found that TRPC1 interacts physically with TRPV4 to form a complex. In functional studies, flow elicited a transient [Ca(2+)](i) increase in TRPV4-expressing human embryonic kidney (HEK) 293 cells. Coexpression of TRPC1 with TRPV4 markedly prolonged this [Ca(2+)](i) transient; it also enabled this [Ca(2+)](i) transient to be negatively modulated by protein kinase G. Furthermore, this flow-induced [Ca(2+)](i) increase was markedly inhibited by anti-TRPC1-blocking antibody T1E3 and a dominant-negative construct TRPC1 Delta 567-793 in TRPV4-C1-coexpressing HEK cells and human umbilical vein endothelial cells. T1E3 also inhibited flow-induced vascular dilation in isolated rat small mesenteric artery segments.

Conclusions: This study shows that TRPC1 interacts physically with TRPV4 to form a complex, and this TRPV4-C1 complex may mediate flow-induced Ca(2+) influx in vascular endothelial cells. The association of TRPC1 with TRPV4 prolongs the flow-induced [Ca(2+)](i) transient, and it also enables this [Ca(2+)](i) transient to be negatively modulated by protein kinase G. This TRPV4-C1 complex plays a key role in flow-induced endothelial Ca(2+) influx.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling* / drug effects
  • Cells, Cultured
  • Cyclic GMP-Dependent Protein Kinases / metabolism
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Fluorescence Resonance Energy Transfer
  • Humans
  • Immunoprecipitation
  • Kinetics
  • Male
  • Membrane Potentials
  • Mesenteric Arteries / metabolism
  • Microscopy, Fluorescence
  • Multiprotein Complexes
  • Mutation
  • Patch-Clamp Techniques
  • Phorbol Esters / pharmacology
  • Protein Binding
  • RNA Interference
  • Rats
  • Rats, Sprague-Dawley
  • TRPC Cation Channels / genetics
  • TRPC Cation Channels / metabolism*
  • TRPV Cation Channels / agonists
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism*
  • Transfection
  • Vasodilation


  • Multiprotein Complexes
  • Phorbol Esters
  • TRPC Cation Channels
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Trpv4 protein, rat
  • transient receptor potential cation channel, subfamily C, member 1
  • phorbol-12,13-didecanoate
  • Cyclic GMP-Dependent Protein Kinases