The Mechanism of KCNE1 Modulation of KCNQ1 Channels

Abstract

The IKs current controls action potential duration in the heart, and abnormal function of this current causes cardiac arrhythmias. The IKs current is carried by the voltage activated KCNQ1 potassium channel associated with KCNE1 β-subunits. 18 years of study have shown that KCNE1 drastically modulates every characteristic of KCNQ1, such that it would appear as if KCNQ1 and KCNQ1+ KCNE1 were completely unrelated channels. However, no coherent mechanism has been provided that can explain all these drastic changes, which are essential for the physiological role of IKs. Here we show that KCNE1 alters the state-dependent interactions (coupling) between the voltage-sensing and pore-gate domains of KCNQ1 and that this sole mechanism is sufficient to explain all these changes. Contrary to conventional belief that the voltage-sensing domain must reach the fully-activated state before promoting pore-opening, we found that the KCNQ1 channels can open when the voltage-sensing domain is at intermediate and fully-activated states. Importantly, the intermediate-open and activated-open channels differ in voltage-dependence, ion-permeation, pharmacology and dependence on PIP2, a cofactor for coupling between the voltage-sensing and pore-gate domains. By changing the coupling, KCNE1 prevents the intermediate-open state and changes the properties of the activated-open state, thereby bringing about the characteristics of the IKs current. These results indicate that, during voltage-dependent ion channel gating, every-state of the voltage-sensing domain along its activation pathway is coupled to the conformation of the pore domain through a unique set of protein-protein and protein-lipid interactions. These interactions determine both the open-probability and the open-pore properties.