BPS2026 – Voltage dependent block of the cardiac potassium channel HERG by extracellular monovalent, divalent, and trivalent cations

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 Ca 2+ , Mg 2+ , and Zn 2+ 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 range of monovalent, divalent and trivalent cations, including H, Ca, Mg, Co, Mn, Ba, Zn, As, and La all reduce HERG current in a voltage dependent manner. In addition, we found that Ca does not block the HERG double mutation G628CS631C, located at the outer entrance to the selectivity filter. We also show that although G628CS631C has some selectivity for sodium, the permeability of G628CS631C to calcium is very low. This suggests that calcium blocks HERG at a site just outside the selectivity filter and raises the possibility that extracellular cations block HERG at a common site just outside the selectivity filter. This could have implications for arsenic-based treatment strategies for acute promyelocytic anemia and highlight emerging health risks associated with the increasing presence in humans of toxic cations such as cadmium.