Interactions of Extracellular Potassium, Calcium, Magnesium and Hydrogen with the outer Pore of the Cardiac Potassium Channel hERG

Abstract

Reduction of the current carried by the cardiac potassium channel HERG can lead to Long QT syndrome, an arrhythmia characterized by a rapid heart rate and reduced cardiac output, which can, in certain situations, be fatal. The effect of extracellular electrolytes on the biophysical properties of the HERG channel have been studied in some detail. In particular, increases in extracellular calcium, magnesium and hydrogen have been shown to slow channel activation, increase channel deactivation, and shift the G-V curve to more positive voltages. A number of reports have also shown that hydrogen can reduce HERG current by a mechanism that does not involve an effect on channel deactivation and which likely involves pore block. We show here that reducing extracellular potassium results in a significant increase in HERG current reduction by extracellular calcium, hydrogen, and magnesium. Current reduction by calcium appears to be significantly greater than current reduction by magnesium. Furthermore, the reduction in HERG current by extracellular hydrogen depended on the extracellular calcium concentration. The Drosophila voltage-gated potassium channel Shaker, showed a much smaller decrease in current by extracellular calcium and this effect was not dependent on extracellular potassium. In addition there was no difference in current reduction by calcium between WT HERG and the inactivation deficient mutant S631A, either in low or high extracellular potassium. These results suggest that calcium, hydrogen, and magnesium can block the HERG potassium channel and that calcium, hydrogen, magnesium, and potassium may interact at the outer pore of the HERG channel.