Regulation of Voltage Sensor Movement in KCNQ Channels by KCNE Beta Subunits

Abstract

The KCNQ1 potassium channel plays widely different physiological roles different cell types. In the heart KCNQ1 forms part of the voltage-gated IKs channels that limit the duration of the cardiac action potential, whereas in epithelial cells KCNQ1 forms part of a voltage-independent K+ channel that is important for ion secretion. The different functions of KCNQ1 are mainly due to the co-assembly of KCNQ1 with different KCNE beta subunits. For example, the IKS channel consists of 4 α-subunits (KCNQ1) which assemble with 2 to 4 β subunits (KCNE1), whereas in epithelial cells KCNQ1 co-assembles with KCNE3 to form voltage-independent K+ channels. Mutations in either KCNQ1 or KCNE1 cause cardiac arrhythmia syndromes. Here we use Voltage clamp fluorometry (VCF) to directly study the effects of wild type and mutant KCNE subunits on the voltage sensor movement in KCNQ1 channel. We assess the voltage sensor movement (fluorescence) and channel opening (current), in order to understand the coupling between the KCNQ1 voltage sensor and channel gate in the presence of KCNE subunits. Our data shows that KCNE1 splits the voltage sensor movement in two separates phases: one at hyperpolarized potentials that moves the voltage sensor to an active state and a second at more depolarized potentials, which is tightly coupled to channel opening. Interestingly, VCF shows that KCNE3 locks the voltage sensor of KCNQ1, presumably in its activated state, thereby generating a voltage-independent K+ channel. Furthermore, arrhythmia-causing mutations in KCNE1 shift the voltage dependence of the two different voltage sensor movements, revealing some of the molecular mechanisms underlying these arrhythmia-causing mutations. Our data suggests a putative mechanism for how KCNE1 subunit exerts its effects on the voltage sensor movement during IKs channel activation.