Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity

The very slowly activating delayed rectifier K^- channel I(Ks) is essential for controlling the repolarization phase of cardiac action potentials and K^- homeostasis in the inner ear. The I(Ks) channel is formed via the assembly of two transmembrane proteins, KvLQT1 and MinK. Mutations in KvLQT1 are associated with a long QT syndrome that causes syncope and sudden death and also with deafness. Here, we show a new mode of association between ion channel forming subunits in that the cytoplasmic C-terminal end of Mink interacts directly with the pore region of KvLQT1. This interaction reduces KvLQT1 channel conductance from 7.6 to 0.58 picosiemens. However, because Mink also reveals a large number of previously silent KvLQT1 channels (x 60), the overall effect is a large increase (x 4) in the macroscopic K^- current. Conformational changes associated with the KvLQT1/MinK association create very slow and complex activation kinetics without much alteration in the deactivation process. Changes induced by Mink have an essential regulatory role in the development of this K^- channel activity upon repetitive electrical stimulation with a particular interest in tachycardia.