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J Biol Chem, Vol. 274, Issue 30, 21063-21070, July 23, 1999

Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits

Laura Franqueza, Monica Lin, Igor Splawski^§¶, Mark T. Keating^§¶, and Michael C. Sanguinetti

From the  Department of Medicine, Division of Cardiology,  Eccles Program in Human Molecular Biology and Genetics, ^§ Howard Hughes Medical Institute, and ^¶ Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112

Long QT syndrome is an inherited disorder of cardiac repolarization caused by mutations in cardiac ion channel genes, including KVLQT1. In this study, the functional consequences of three long QT-associated missense mutations in KvLQT1 (R243C, W248R, E261K) were characterized using the Xenopus oocyte heterologous expression system and two-microelectrode voltage clamp techniques. These mutations are located in or near the intracellular linker between the S4 and S5 transmembrane domains, a region implicated in activation gating of potassium channels. The E261K mutation caused loss of function and did not interact with wild-type KvLQT1 subunits. R243C or W248R KvLQT1 subunits formed functional channels, but compared with wild-type KvLQT1 current, the rate of activation was slower, and the voltage dependence of activation and inactivation was shifted to more positive potentials. Co expression of minK and KvLQT1 channel subunits induces a slow delayed rectifier K⁺ current, I_Ks, characterized by slow activation and a markedly increased magnitude compared with current induced by KvLQT1 subunits alone. Coexpression of minK with R243C or W248R KvLQT1 subunits suppressed current, suggesting that coassembly of mutant subunits with minK prevented normal channel gating. The decrease in I_Ks caused by loss of function or altered gating properties explains the prolonged QT interval and increased risk of arrhythmia and sudden death associated with these mutations in KVLQT1.

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