Molecular Mechanism of QT Prolongation due to dysfunction of HERG K^+ Channels

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HERG encodes Ikr current, an important factor for cardiac repolarization and gene defects in HERG cause one form of inherited long QT syndrome (LQT2). HERG/Ikr currents are the targets of various cardiac and non-cardiac drugs that causes drug-induced long QT syndrome. We studied molecular mechanism of HERG current suppression in gene defects found in LQT2 families and by factors known to block Ikr currents. Functional abnormality ofHERG mutations in T474I, A614V and V630L were analyzed using heterologous expression system in Xenopus oocytes. The mutant alone could not express current, but co-injection with wild type and each mutant produced dominant negative suppression (DNS) with its degree increasing in the order of V63OL>A614V>T474I.V60L and A614V further produced negative shift in steady state inactivation curve and fastened inactivation. We next analyzed R534C mutation in S4, presumed voltage sensor. R534C shifted voltage-dependent activation confirming S4 playing as voltage sensor, and produced fast deactivation. But, fast deactivation could not explain the reason for QT prolongation in R534C, suggesting the presence of another unknown factor. The mutation in HERG C-terminus, S818L, did not express the current by mutant alone and co-injection with wild type did not show DNS.However co-injection of wild type and excess amount of cRNA of S818L produced DNS and shifted activation curve with fast activation and deactivation kinetics. The results suggest that S818L can form heteromultimer with wild type to yield functional channels with wild type, and that the C-terminus of HERG may participate in activation process of this channels. Therefore, various types and locations of HERG mutaions cause current suppression with different mechanisms. We also explored acidosis-induced suppression of HERG current due mainly to effects on activation process.