Interactions of Extracellular Divalent Ions 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 a number of extracellular divalent ions, including calcium, magnesium, cobalt, manganese, and hydrogen. The potency of current reduction is different for each ion tested, with cobalt showing the greatest current reduction and magnesium the least. The Drosophila voltage-gated potassium channel Shaker and two voltage-gated potassium channels closely related to HERG, EAG and ELK, showed a much smaller decrease in current by extracellular calcium compared to HERG and this effect was not as strongly dependent on extracellular potassium. 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. However, current reduction by calcium was decreased compared to WT in the mutant G628CS631C. These results suggest that various divalent ions can block HERG with different potencies and may interact at the outer pore of the HERG channel.