Enhancement of HERG K+ currents by Cd2+ destabilization of the inactivated state

Biophys J. 1999 Nov;77(5):2534-41. doi: 10.1016/s0006-3495(99)77088-8.

Abstract

We have studied the functional effects of extracellular Cd(2+) on human ether-a-go-go-related gene (HERG) encoded K(+) channels. Low concentrations (10-200 microM) of extracellular Cd(2+) increased outward currents through HERG channels; 200 microM Cd(2+) more than doubled HERG currents and altered current kinetics. Cd(2+) concentrations up to 200 microM did not change the voltage dependence of channel activation, but shifted the voltage dependence of inactivation to more depolarized membrane potentials. Cd(2+) concentrations >or=500 microM shifted the voltage dependence of channel activation to more positive potentials. These results are consistent with a somewhat specific ability of Cd(2+) to destabilize the inactivated state. We tested the hypothesis that channel inactivation is essential for Cd(2+)-induced increases in HERG K(+) currents, using a double point mutation (G628C/S631C) that diminishes HERG inactivation (Smith, P. L., T. Baukrowitz, and G. Yellen. 1996. Nature (Lond.). 379:833-836). This inactivation-removed mutant is insensitive to low concentrations of Cd(2+). Thus, Cd(2+) had two distinct effects on HERG K(+) channels. Low concentrations of Cd(2+) caused relatively selective effects on inactivation, resulting in a reduction of the apparent rectification of the channel and thereby increasing HERG K(+) currents. Higher Cd(2+) concentrations affected activation gating as well, possibly by a surface charge screening mechanism or by association with a lower affinity site.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Binding Sites
  • CHO Cells
  • Cadmium / metabolism
  • Cadmium / pharmacology*
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • ERG1 Potassium Channel
  • Electric Conductivity*
  • Ether-A-Go-Go Potassium Channels / chemistry*
  • Ether-A-Go-Go Potassium Channels / genetics
  • Ether-A-Go-Go Potassium Channels / metabolism*
  • Extracellular Space / metabolism
  • Humans
  • Ion Channel Gating / drug effects
  • Kinetics
  • Mutation
  • Potassium / metabolism*
  • Protein Stability / drug effects

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • KCNH2 protein, human
  • Cadmium
  • Potassium