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

Yang Li, Mark A. Zaydman, Dick Wu, Jingyi Shi, Michael Guan, Brett Virgin-Downey, Jianmin Cui

Research output: Contribution to journalArticlepeer-review

92 Scopus citations

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP2) is necessary for the function of various ion channels. The potassium channel, IKs, is important for cardiac repolarization and requires PIP2 to activate. Here we show that the auxiliary subunit of IKs, 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 IKs channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.

Original languageEnglish
Pages (from-to)9095-9100
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number22
DOIs
StatePublished - May 31 2011

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