TRPC5 is a Ca2+-activated channel functionally coupled to Ca2+-selective ion channels

J Biol Chem. 2009 Dec 4;284(49):34423-32. doi: 10.1074/jbc.M109.018192. Epub 2009 Oct 8.


TRPC5 forms non-selective cation channels. Here we studied the role of internal Ca(2+) in the activation of murine TRPC5 heterologously expressed in human embryonic kidney cells. Cell dialysis with various Ca(2+) concentrations (Ca(2+)(i)) revealed a dose-dependent activation of TRPC5 channels by internal Ca(2+) with EC(50) of 635.1 and 358.2 nm at negative and positive membrane potentials, respectively. Stepwise increases of Ca(2+)(i) induced by photolysis of caged Ca(2+) showed that the Ca(2+) activation of TRPC5 channels follows a rapid exponential time course with a time constant of 8.6 +/- 0.2 ms at Ca(2+)(i) below 10 microM, suggesting that the action of internal Ca(2+) is a primary mechanism in the activation of TRPC5 channels. A second slow activation phase with a time to peak of 1.4 +/- 0.1 s was also observed at Ca(2+)(i) above 10 microM. In support of a Ca(2+)-activation mechanism, the thapsigargin-induced release of Ca(2+) from internal stores activated TRPC5 channels transiently, and the subsequent Ca(2+) entry produced a sustained TRPC5 activation, which in turn supported a long-lasting membrane depolarization. By co-expressing STIM1 plus ORAI1 or the alpha(1)C and beta(2) subunits of L-type Ca(2+) channels, we found that Ca(2+) entry through either calcium-release-activated-calcium or voltage-dependent Ca(2+) channels is sufficient for TRPC5 channel activation. The Ca(2+) entry activated TRPC5 channels under buffering of internal Ca(2+) with EGTA but not with BAPTA. Our data support the hypothesis that TRPC5 forms Ca(2+)-activated cation channels that are functionally coupled to Ca(2+)-selective ion channels through local Ca(2+) increases beneath the plasma membrane.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / chemistry
  • Calcium / metabolism
  • Cell Line
  • Cell Membrane / metabolism
  • Chelating Agents / pharmacology
  • Humans
  • Ion Channels / chemistry*
  • Ions
  • Membrane Potentials
  • Mice
  • Models, Biological
  • TRPC Cation Channels / metabolism*
  • TRPC Cation Channels / physiology
  • Thapsigargin / chemistry
  • Time Factors


  • Chelating Agents
  • Ion Channels
  • Ions
  • TRPC Cation Channels
  • TRPC5 protein, human
  • Trpc5 protein, mouse
  • Thapsigargin
  • Calcium