IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits Journal Article

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Authors: Ruscic, K. J.; Miceli, F.; Villalba-Galea, C. A.; Dai, H.; Mishina, Y.; Bezanilla, F.; Goldstein, S. A.
Article Title: IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits
Abstract: Human I(Ks) channels activate slowly with the onset of cardiac action potentials to repolarize the myocardium. I(Ks) channels are composed of KCNQ1 (Q1) pore-forming subunits that carry S4 voltage-sensor segments and KCNE1 (E1) accessory subunits. Together, Q1 and E1 subunits recapitulate the conductive and kinetic properties of I(Ks). How E1 modulates Q1 has been unclear. Investigators have variously posited that E1 slows the movement of S4 segments, slows opening and closing of the conduction pore, or modifies both aspects of electromechanical coupling. Here, we show that Q1 gating current can be resolved in the absence of E1, but not in its presence, consistent with slowed movement of the voltage sensor. E1 was directly demonstrated to slow S4 movement with a fluorescent probe on the Q1 voltage sensor. Direct correlation of the kinetics of S4 motion and ionic current indicated that slowing of sensor movement by E1 was both necessary and sufficient to determine the slow-activation time course of I(Ks).
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 110
Issue: 7
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2013
Start Page: E559
End Page: 66
Language: eng
DOI/URL:

10.1073/pnas.1222616110
Notes: LR: 20161019; GR: T32 GM007281/GM/NIGMS NIH HHS/United States; GR: R01 GM030376/GM/NIGMS NIH HHS/United States; GR: R01GM030376/GM/NIGMS NIH HHS/United States; GR: T32GM7281/GM/NIGMS NIH HHS/United States; GR: R01 HL105949/HL/NHLBI NIH HHS/United States; GR: R01HL105959/HL/NHLBI NIH HHS/United States; JID: 7505876; 0 (Intermediate-Conductance Calcium-Activated Potassium Channels); 0 (KCNE1 protein, human); 0 (KCNQ1 Potassium Channel); 0 (KCNQ1 protein, human); 0 (Potassium Channels, Voltage-Gated); 0 (Protein Subunits); OID: NLM: PMC3574954; ppublish