The cardiac potassium channel HERG is blocked by calcium at a site near the outer mouth of the channel

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A reduction in the number of HERG channels has been implicated in Long QT Syndrome, which can degenerate into the lethal arrhythmia Torsades de Pointes. Patients can present with abnormal serum electrolyte levels due to a variety of conditions including gastrointestinal dysfunction, renal and endocrine disorders, diuretic use, alcoholism, and aging. The aim of this study is to determine if extracellular calcium blocks the pore of the HERG channel by acting at a site in the outer vestibule of the channel.Divalent block was measured using two‐electrode voltage clamping of Xenopus oocytes expressing either wild‐type HERG or the HERG mutants S631A, and G628CS631C. S631 is thought to be located in the outer pore of the HERG channel.Changing extracellular potassium from 0 mM to 20 mM resulted in a greater decrease in WT HERG current due to an increase in extracellular calcium, as well as a number of other divalent ions (Mg2+, Co2+ and Mn2+). In addition, block of WT HERG by calcium was voltage dependent, with increased block at negative voltages. Finally, there was little or no block of the HERG double mutant G628CS631C by calcium at all voltages tested, whereas there was increased block of the HERG mutant S631A by calcium at negative voltages.3 results suggest that calcium blocks HERG by physically occluding the pore of the channel: 1) the dependence of block on extracellular potassium. 2) the lack of block of G628CS631C 3) the altered voltage dependence of block of S631A. This study has implications for an increased risk of cardiac arrhythmias with hypokalemia as well as for patients with acute promyelocitic leukemia treated with arsenic, a trivalent ion that might block HERG at the same site as calcium.Funded by Touro University and NIHR 15‐1R15HL079971