IKs channels open slowly because KCNE1 accessory subunits slow the movement of S4 voltage sensors in KCNQ1 pore-forming subunits.
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).
Department of Biochemistry, Brandeis University, Waltham, MA 02454, USA.
Katarina J
KJ
Ruscic
Francesco
F
Miceli
Carlos A
CA
Villalba-Galea
Hui
H
Dai
Yukiko
Y
Mishina
Francisco
F
Bezanilla
Steve A N
SA
Goldstein
D007758:Ear, Inner / Q000378:metabolism*; D004553:Electric Conductivity; D005453:Fluorescence; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D056969:Voltage-Sensitive Dye Imaging
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits