Enhancement of HERG K+ Currents by Cd2+ Destabilization of the Inactivated State
| Autor: | Paul B. Bennett, J. P. Johnson, Jeffrey R. Balser |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
ERG1 Potassium Channel
congenital hereditary and neonatal diseases and abnormalities Stereochemistry Mutant Kinetics hERG Biophysics CHO Cells Gating Cricetulus Cricetinae Extracellular Animals Humans cardiovascular diseases Binding site Membrane potential Binding Sites Dose-Response Relationship Drug biology Protein Stability Chemistry Electric Conductivity Ether-A-Go-Go Potassium Channels Mutation Potassium biology.protein Extracellular Space Ion Channel Gating Cadmium Research Article |
| Zdroj: | Biophysical Journal. 77:2534-2541 |
| ISSN: | 0006-3495 |
| DOI: | 10.1016/s0006-3495(99)77088-8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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