Interactions of Extracellular Potassium, Calcium 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 deactivation. In addition, 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 may involve pore block. We show here that reducing extracellular potassium results in a significant increase in HERG current reduction by both extracellular calcium and hydrogen. 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. Furthermore, the reduction in HERG current by extracellular hydrogen depended on the extracellular calcium concentration. Taken together these results suggest that calcium and hydrogen can block the HERG potassium channel and that calcium, hydrogen, and potassium may interact at the outer pore of the HERG channel. These extracellular electrolyte effects may be specific to the HERG channel.