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External protons destabilize the activated voltage sensor in hERG channels.

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Extracellular acidosis affects hERG channel gating. Protons bind to acidic residues D456, D460, and D509, disrupting S4 interactions and shifting activation potentials.

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Area of Science:

  • Cardiovascular physiology
  • Ion channel biophysics
  • Molecular pharmacology

Background:

  • Extracellular acidosis alters hERG channel activation and deactivation.
  • Divalent cations like Ca(2+) and Cd(2+) mimic these effects.
  • A metal ion binding pocket involving D456, D460, and D509 is implicated.

Purpose of the Study:

  • To elucidate the mechanisms of proton and divalent cation effects on hERG channel gating.
  • To identify the specific residues and interactions responsible for pH-dependent hERG channel activation.

Main Methods:

  • Two-electrode voltage clamp electrophysiology.
  • Site-directed mutagenesis of hERG channel residues.
  • Voltage-clamp fluorimetry to track S4 movement.

Main Results:

  • Proton sensitivity of hERG activation (pKa = 5.6) was reduced by Cd(2+), suggesting a shared binding site.
  • Mutational analysis confirmed D509, D456, and D460 are critical for pH-dependent activation.
  • Neutralization of these residues abolished proton-induced activation shifts.
  • Protons shifted S4 movement to more depolarized potentials.

Conclusions:

  • The metal ion binding pocket (D456, D460, D509) mediates proton effects on hERG activation.
  • Protonation disrupts interactions between these residues and S4 gating charges.
  • This destabilizes the activated S4 configuration, explaining the observed gating shifts.