KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity

被引：88

作者：

Li, Yang ^{[1
]}

Zaydman, Mark A. ^{[1
]}

Wu, Dick ^{[1
]}

Shi, Jingyi ^{[1
]}

Guan, Michael ^{[1
]}

Virgin-Downey, Brett ^{[1
]}

Cui, Jianmin ^{[1
]}

机构：

[1] Washington Univ, Dept Biomed Engn, Ctr Invest Membrane Excitabil Disorders, Cardiac Bioelectr & Arrhythmia Ctr, St Louis, MO 63130 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2011年 / 108卷 / 22期

基金：

美国国家科学基金会;

关键词：

RECEPTOR-MEDIATED INHIBITION; MINK-RELATED PEPTIDE-1; POTASSIUM CHANNELS; BETA-SUBUNIT; K+ CHANNEL; KCNQ1; MEMBRANE; MUTATIONS; KCNQ1-KCNE1; PROTEINS;

D O I：

10.1073/pnas.1100872108

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Phosphatidylinositol 4,5-bisphosphate (PIP2) is necessary for the function of various ion channels. The potassium channel, I-Ks, is important for cardiac repolarization and requires PIP2 to activate. Here we show that the auxiliary subunit of I-Ks, KCNE1, increases PIP2 sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP2 levels in the membrane are insufficient to activate all KCNQ1 channels. A juxtamembranous site in the KCNE1 C terminus is a key structural determinant of PIP2 sensitivity. Long QT syndrome associated mutations of this site lower PIP2 affinity, resulting in reduced current. Application of exogenous PIP2 to these mutants restores wild-type channel activity. These results reveal a vital role of PIP2 for KCNE1 modulation of I-Ks channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.

引用

页码：9095 / 9100

页数：6

共 53 条

[1] Disease-associated mutations in KCNE potassium channel subunits (MiRPs) reveal promiscuous disruption of multiple currents and conservation of mechanism [J].