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Receptor-mediated regulation of the nonselective cation channels TRPC4 and TRPC5

M Schaefer1, T D Plant, A G Obukhov

  • 1Institut für Pharmakologie, Freie Universität Berlin, Thielallee 69-73, 14195 Berlin, Germany.

The Journal of Biological Chemistry
|June 6, 2000
PubMed

Insights

Transient Receptor Potential Channels (TRPCs) TRPC4 and TRPC5 are nonselective cation channels activated by G-protein-coupled receptors and tyrosine kinases, independent of intracellular calcium stores. Their properties differ from store-operated currents.

Area of Science:

  • Molecular and Cellular Biology
  • Ion Channel Physiology
  • Biophysics

Background:

  • Mammalian Transient Receptor Potential Channels (TRPCs) are Ca(2+)-permeable cation channels, with TRPC1-TRPC7 identified.
  • TRPC channels are implicated as molecular correlates for capacitative calcium entry.
  • Limited research exists on TRPC4 and TRPC5 subfamily regulation, with conflicting data on store depletion's role in activation.

Purpose of the Study:

  • To investigate the regulatory and biophysical properties of murine TRPC4 and TRPC5 (mTRPC4/5).
  • To clarify the role of intracellular Ca(2+) store depletion in mTRPC4/5 channel activation.

Main Methods:

  • Heterologous expression of mTRPC4/5 in human embryonic kidney cells.
  • Measurement of Mn(2+) entry using fura-2 fluorescence.
  • Whole-cell and inside-out patch-clamp electrophysiology.
  • Stimulation via G(q/11)-coupled receptors, receptor tyrosine kinases, and GTPgammaS.

Main Results:

  • Activation of G(q/11)-coupled receptors or receptor tyrosine kinases induced Mn(2+) entry in mTRPC4/5-expressing cells.
  • GTPgammaS mimicked receptor stimulation, evoking large, nonselective cation currents.
  • Intracellular Ca(2+) store depletion failed to activate mTRPC4/5 channels.
  • Single mTRPC4 and mTRPC5 channels exhibited conductances of 42 and 66 pS, respectively, and were stimulated by GTPgammaS in a membrane-confined manner.
  • mTRPC4/5 biophysical properties are distinct from I(CRAC).

Conclusions:

  • Murine TRPC4 and TRPC5 form nonselective cation channels.
  • These channels integrate signaling from G-protein-coupled receptors and receptor tyrosine kinases independently of intracellular store depletion.
  • The biophysical characteristics of mTRPC4/5 do not align with the store-operated current I(CRAC).

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