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A residue in the TRPM2 channel outer pore is crucial in determining species-dependent sensitivity to extracellular

Jie Zou1, Wei Yang, David J Beech

  • 1Institute of Membrane and Systems Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK.

Pflugers Archiv : European Journal of Physiology
|April 21, 2011
PubMed

Insights

Extracellular acidic pH reversibly inhibits human TRPM2 (transient receptor potential melastatin 2) channels, leading to irreversible inactivation with prolonged exposure. A specific residue in the outer pore determines species-dependent pH sensitivity.

Area of Science:

  • Ion channel physiology
  • Molecular biology
  • Biophysics

Background:

  • Acidic pH is a critical regulator of ion channel function.
  • TRPM2 channels play roles in various biological processes.
  • Species-specific differences in ion channel behavior are common.

Purpose of the Study:

  • To investigate the inhibition of human TRPM2 channels by extracellular acidic pH.
  • To compare the sensitivity of human (h) and mouse (m) TRPM2 channels to acidic pH.
  • To identify the molecular determinants of species-dependent pH inhibition in TRPM2 channels.

Main Methods:

  • Electrophysiological recordings of hTRPM2 and mTRPM2 channel currents.
  • Application of varying extracellular acidic pH levels.
  • Site-directed mutagenesis of the TRPM2 channel pore region.

Main Results:

  • Extracellular acidic pH induced reversible inhibition followed by irreversible inactivation of hTRPM2 channels.
  • mTRPM2 channels showed slower inhibition kinetics and were less sensitive to acidic pH compared to hTRPM2 channels.
  • Mutating Gln(992) in mTRPM2 to His(995) (found in hTRPM2) conferred hTRPM2-like pH sensitivity and kinetics, while the reciprocal mutation in hTRPM2 slowed inhibition.

Conclusions:

  • Extracellular acidic pH affects TRPM2 channel activity through both reversible and irreversible mechanisms.
  • Species-dependent differences in TRPM2 channel inhibition by acidic pH exist.
  • Residue His(995)/Gln(992) in the outer pore is crucial for determining the species-specific response of TRPM2 channels to extracellular acidic pH.

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