KCNE1 divides the voltage sensor movement in KCNQ1/KCNE1 channels into two steps.
The functional properties of KCNQ1 channels are highly dependent on associated KCNE-β subunits. Mutations in KCNQ1 or KCNE subunits can cause congenital channelopathies, such as deafness, cardiac arrhythmias and epilepsy. The mechanism by which KCNE1-β subunits slow the kinetics of KCNQ1 channels is a matter of current controversy. Here we show that KCNQ1/KCNE1 channel activation occurs in two steps: first, mutually independent voltage sensor movements in the four KCNQ1 subunits generate the main gating charge movement and underlie the initial delay in the activation time course of KCNQ1/KCNE1 currents. Second, a slower and concerted conformational change of all four voltage sensors and the gate, which opens the KCNQ1/KCNE1 channel. Our data show that KCNE1 divides the voltage sensor movement into two steps with widely different voltage dependences and kinetics. The two voltage sensor steps in KCNQ1/KCNE1 channels can be pharmacologically isolated and further separated by a disease-causing mutation.
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Rene
R
Barro-Soria
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Santiago
S
Rebolledo
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Sara I
SI
Liin
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
Marta E
ME
Perez
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Kevin J
KJ
Sampson
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York, New York 10032, USA.
Robert S
RS
Kass
Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida 33136, USA.
H Peter
HP
Larsson
D005453:Fluorescence; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics / Q000502:physiology*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D007700:Kinetics; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D021122:Protein Subunits / Q000378:metabolism
C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits