functional interactions between kcne1 c-terminus and the kcnq1 channel功能之间的交互kcne1糖和kcnq1通道.pdfVIP

Functional Interactions between KCNE1 C-Terminus and the KCNQ1 Channel 2 1 3 1,2 Jerri Chen , Renjian Zheng , Yonathan F. Melman , Thomas V. McDonald * 1 Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, United States of America, 2 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, United States of America, 3 Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America Abstract The KCNE1 gene product (minK protein) associates with the cardiac KvLQT1 potassium channel (encoded by KCNQ1) to create the cardiac slowly activating delayed rectifier, IKs. Mutations throughout both genes are linked to the hereditary cardiac arrhythmias in the Long QT Syndrome (LQTS). KCNE1 exerts its specific regulation of KCNQ1 activation via interactions between membrane-spanning segments of the two proteins. Less detailed attention has been focused on the role of the KCNE1 C-terminus in regulating channel behavior. We analyzed the effects of an LQT5 point mutation (D76N) and the truncation of the entire C-terminus (D70) on channel regulation, assembly and interaction. Both mutations significantly shifted voltage dependence of activation in the depolarizing direction and decreased IKs current density. They also accelerated rates of channel deactivation but notably, did not affect activation kinetics. Truncation of the C-terminus reduced the apparent affinity of KCNE1 for KCNQ1, resulting in impaired channel formation and presentation of KCNQ1/ KCNE1 complexes to the surface. Complete saturation of KCNQ1 channels with KCNE1-D70 could be achieved by relativ