Molecular mechanism and functional significance of the MinK control of the KvLQT1 channel activity.
The very slowly activating delayed rectifier K+ channel IKs is essential for controlling the repolarization phase of cardiac action potentials and K+ homeostasis in the inner ear. The IKs channel is formed via the assembly of two transmembrane proteins, KvLQT1 and MinK. Mutations in KvLQT1 are associated with a long QT syndrome that causes syncope and sudden death and also with deafness. Here, we show a new mode of association between ion channel forming subunits in that the cytoplasmic C-terminal end of MinK interacts directly with the pore region of KvLQT1. This interaction reduces KvLQT1 channel conductance from 7.6 to 0.58 picosiemens. However, because MinK also reveals a large number of previously silent KvLQT1 channels (x 60), the overall effect is a large increase (x 4) in the macroscopic K+ current. Conformational changes associated with the KvLQT1/MinK association create very slow and complex activation kinetics without much alteration in the deactivation process. Changes induced by MinK have an essential regulatory role in the development of this K+ channel activity upon repetitive electrical stimulation with a particular interest in tachycardia.
Romey
G
G
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, 660 route des Lucioles, Sophia Antipolis, 06560 Valbonne, France.
Attali
B
B
Chouabe
C
C
Abitbol
I
I
Guillemare
E
E
Barhanin
J
J
Lazdunski
M
M
D000200:Action Potentials; D000818:Animals; D019556:COS Cells; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D007700:Kinetics; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding; D014162:Transfection
D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk)