State‐dependent barium block of wild‐type and inactivation‐deficient HERG channels in Xenopus oocytes

1 The effects of Ba2+ on current resulting from the heterologous expression of the human ether‐à‐go‐go related gene (HERG) (IHERG) was studied with two‐electrode voltage clamp techniques in Xenopus oocytes. 2 Ba2+ produced time‐ and voltage‐dependent block of IHERG. Significant inhibition was seen at concentrations as low as 1 μm. Inhibition was greatest at step potentials between ‐40 and 0 mV; at more positive potentials, inhibition decreased in association with time‐dependent unblocking of channels. 3 An inactivation‐attenuated mutant of HERG (S631A) was prepared and expressed in Xenopus oocytes. Ba2+ block of S631A differed from that of HERG in that extensive unblocking was no longer seen at positive potentials and the voltage dependence of step current block was greatly attenuated. 4 A mathematical model was applied to analyse quantitatively the inhibitory effects of Ba2+ on IHERG. The model suggested similar voltage‐dependent affinity of Ba2+ for the open and closed states, along with absence of binding to the inactivated state, and accounted well for Ba2+ effects on both wild‐type and S631A channels. 5 We conclude that Ba2+ potently inhibits IHERG in a characteristic state‐dependent fashion, with strong unblocking at positive potentials related to the presence of an intact C‐type inactivation mechanism.

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