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Modulation of HERG potassium channels by extracellular magnesium and quinidine
1Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6602, USA.
Abstract:
Torsades de pointes is a polymorphic ventricular arrhythmia resulting from congenital or drug-induced (acquired) QT prolongation. Pharmacologic suppression of repolarizing potassium currents is one mechanism causing the acquired long QT (LQT) syndrome. Recent studies have linked mutations in a gene encoding a potassium channel subunit (HERG) to the LQT syndrome. Clinical experience indicates that intravenous magnesium sulfate is effective in reversing torsades de pointes, but the molecular basis of this effect is not understood. This study was designed to investigate the effects of extracellular magnesium (Mg2+) on HERG potassium currents. HERG potassium channels were expressed in Xenopus oocytes and in a human cell line and were examined by voltage-clamp methods. Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent shift in the membrane-potential dependence of HERG channel opening, causing a reduction in K+ current. This effect was much greater than that observed in another human delayed rectifier K+ channel, hKv1.5, suggesting a specific interaction with the HERG channel. Quinidine is an antiarrhythmic drug that also causes torsades de pointes under certain conditions. Quinidine (3 microM) inhibited HERG currents expressed in oocytes by 32.1 +/- 3.2% (n = 5), whereas 1 microM quinidine inhibited HERG currents in tsA201 cells by 75.8 +/- 2.4% (n = 12). Increasing extracellular Mg2+ did not relieve the inhibition by quinidine, but caused additional suppression. These results indicate that extracellular Mg2+ exerts a direct action on HERG potassium channels, resulting in suppression of outward repolarizing potassium current. It is concluded that modulation of this important K+ current is not the mechanism by which intravenous magnesium terminates drug-induced LQT and torsades de pointes. Potent suppression of HERG channel current by quinidine, compared with that of I(Ks) and I(Na), is a likely contributor to torsades de pointes arrhythmias.
Insights
Extracellular magnesium (Mg2+) directly suppresses HERG potassium currents, a key factor in long QT syndrome. This finding suggests Mg2+ does not reverse torsades de pointes by modulating this specific current.
Area of Science:
- Molecular Cardiology
- Electrophysiology
- Pharmacology
Background:
- Torsades de pointes (TdP) is a life-threatening arrhythmia linked to QT prolongation, often caused by drug-induced long QT (LQT) syndrome.
- Suppression of repolarizing potassium currents, particularly HERG (human Ether-à-go-go-Related Gene), is a known mechanism for acquired LQT.
- Intravenous magnesium sulfate effectively treats TdP, but its molecular mechanism remains unclear.
Purpose of the Study:
- To investigate the direct effects of extracellular magnesium (Mg2+) on HERG potassium channel function.
- To explore the interaction between Mg2+, HERG channels, and the antiarrhythmic drug quinidine in the context of TdP.
Main Methods:
- HERG potassium channels were expressed in Xenopus oocytes and a human cell line (tsA201).
- Voltage-clamp techniques were used to measure HERG channel currents.
- The impact of varying extracellular Mg2+ concentrations and quinidine on HERG currents was assessed.
Main Results:
- Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent reduction in HERG K+ current by altering channel gating.
- This Mg2+ effect was more pronounced on HERG channels compared to hKv1.5 channels, indicating specificity.
- Quinidine significantly inhibited HERG currents; increasing Mg2+ further suppressed currents without reversing quinidine's effect.
Conclusions:
- Extracellular Mg2+ directly suppresses HERG potassium channel activity, reducing outward repolarizing current.
- This direct Mg2+ action on HERG channels is unlikely to be the primary mechanism for terminating drug-induced TdP.
- Potent inhibition of HERG channels by quinidine is a likely contributor to TdP arrhythmias.