Block of the Cardiac Potassium Channel HERG by Cations

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 effects of various extracellular electrolytes on the biophysical properties of the HERG channel have been studied in some detail. In particular, increases in extracellular divalent ions such as Ca2+, Mg2+, and Zn2+ as well as increases in extracellular H+ 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 H+ can reduce HERG current by a mechanism that does not involve an effect on channel deactivation and which may involve pore block. We have found that a number of divalent and trivalent cations, including Ca2+, Mg2+, Co2+, Mn2+, Ba2+, Zn2+, La3+ and Ar3+ all reduce HERG current. All of the cations test for potassium dependency of current reduction show decreased current reduction with increased extracellular potassium. All of the cations tested for voltage-dependent current reduction, reduce WT current in a voltage dependent manner. We also found that current reduction of the double mutant G628S631C by H+, Ca2+ and Ba2+ is reduced compared to current reduction of WT HERG by these cations, whereas current reduction of the double mutant by Zn2+ is increased compared to current reduction of WT by Zn2+. Combined, these data suggest that H+, divalent ions, trivalent all block the pore of HERG, possibly at the same or nearby site in the outer mouth of the channel.