The KCNE1 Subunit Modifies S2-S4 Interactions in the KCNQ1 Subunit of the IKs Channel Complex

Abstract

The IKs channel is formed by the coexpression of KCNE1 with KCNQ1. KCNE1 modifies KCNQ1 to bring about the characteristic IKs current that is essential for terminating ventricular action potentials. The objective of this study is to examine how KCNE1 modifies channel activation by altering the interactions between S2 and S4 in the voltage sensing domain (VSD) of KCNQ1. S2 and S4 contain a series of negatively (E1, E2) and positively (R1, R2, R4) charged residues conserved across all Kv channels, which are essential for voltage-dependent activation. We tested the accessibility of E1C by MTS reagents and found that E1C can be modified by MTSES- only when KCNE1 is present, suggesting that KCNE1 changes the packing of E1C. Likewise, E2 interactions are also altered by KCNE1. E2Q generates constitutively open channels with apparent partial inactivation, a phenotype distinctly different from WT KCNQ1. However, coexpressing E2Q with KCNE1 produces channels that are nearly identical to WT IKs in activation and deactivation, as if the drastic perturbations caused by E2Q in KCNQ1 were inconsequential to the function of IKs. Consistent with this view, in KCNQ1 a secondary mutation R2E can rescue the non-functional E2R. However, this double mutant remains non-functional in the presence of KCNE1. Therefore, E2 and R2 interact in KCNQ1 but not when the channel is coexpressed with KCNE1. Taken together, our data indicate that the association of KCNE1 either directly or allosterically changes the environment around E1 and breaks the interaction between E2 in S2 and R2 in S4. These findings offer new insight into the impact of KCNE1 on the structure of the VSD in KCNQ1, revealing a novel mechanism by which KCNE1 may modulate voltage-dependent activation in KCNQ1.