Domain–domain interactions determine the gating, permeation, pharmacology, and subunit modulation of the IKs ion channel

Abstract

Voltage-gated ion channels generate electrical currents that control muscle contraction, encode neuronal information, and trigger hormonal release. Tissue-specific expression of accessory (β) subunits causes these channels to generate currents with distinct properties. In the heart, KCNQ1 voltage-gated potassium channels coassemble with KCNE1 β-subunits to generate the IKs current (<xref ref-type="bibr" rid="bib3">Barhanin et al., 1996</xref>; <xref ref-type="bibr" rid="bib57">Sanguinetti et al., 1996</xref>), an important current for maintenance of stable heart rhythms. KCNE1 significantly modulates the gating, permeation, and pharmacology of KCNQ1 (<xref ref-type="bibr" rid="bib77">Wrobel et al., 2012</xref>; <xref ref-type="bibr" rid="bib66">Sun et al., 2012</xref>; <xref ref-type="bibr" rid="bib1">Abbott, 2014</xref>). These changes are essential for the physiological role of IKs (<xref ref-type="bibr" rid="bib62">Silva and Rudy, 2005</xref>); however, after 18 years of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent interactions that functionally couple the voltage-sensing domains (VSDs) to the pore.