Divalent Ions and H+ Block the Cardiac Potassium Channel HERG at an Outer Pore Site

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 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 calcium, magnesium, and zinc as well as increases in extracellular 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 have previously described experiments which suggest that there are two separate binding sites on HERG for calcium: one site that interacts with the voltage sensor and one site that may interact with the outer pore of the channel. Here we show, consistent with previously described experiments by others, that H+ and Zn2+ also block HERG in a voltage dependent manner. We found that block of the double mutant G628S631C by H+ is reduced compared to block WT HERG by H+. We also found that arsenic trioxide blocks HERG at negative voltages, although at higher concentrations than previously tested by others. Combined, these data suggest that divalent ions, H+, and possibly arsenic, all block the pore of HERG, possibly at the same or nearby site in the outer mouth of the channel.