Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits

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 oocyt e heterologous expression system and two-microelectrode voltage clamp techn iques. These mutations are located in or near the intracellular linker betw een the S4 and S5 transmembrane domains, a region implicated in activation gating of potassium channels. The E261K mutation caused loss of function an d did not interact with wildtype KvLQT1 subunits, R243C or W248R KVLQT1 sub units formed functional channels, but compared with wild-type KVLQT1 curren t, the rate of activation was slower, and the voltage dependence of activat ion and inactivation was shifted to more positive potentials. Co expression of minK and KvLQT1 channel subunits induces a slow delayed rectifier K+ cu rrent, I-Ks, characterized by slow activation and a markedly increased magn itude 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 gatin g. The decrease in I-Ks caused by loss of function or altered gating proper ties explains the prolonged QT interval and increased risk of arrhythmia an d sudden death associated with these mutations in KVLQT1.