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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (22), p.9095-9100
• Main Authors: Li, Yang, Zaydman, Mark A., Wu, Dick, Shi, Jingyi, Guan, Michael, Virgin-Downey, Brett, Cui, Jianmin
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological Sciences; Channels; Humans; Ions; KCNQ1 Potassium Channel - metabolism; Lipids - chemistry; Long QT Syndrome - genetics; Molecular Sequence Data; Mutation; Mutations; Patch-Clamp Techniques; Phosphatidylinositol 4,5-Diphosphate - metabolism; Potassium; Potassium Channels - chemistry; Potassium Channels, Voltage-Gated - metabolism; Protein Structure, Tertiary; Sequence Homology, Amino Acid; Symptoms; Xenopus laevis; Xenopus Proteins - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1100872108

Phosphatidylinositol 4,5-bisphosphate (PIP 2 ) is necessary for the function of various ion channels. The potassium channel, I Ks , is important for cardiac repolarization and requires PIP 2 to activate. Here we show that the auxiliary subunit of I Ks , KCNE1, increases PIP 2 sensitivity 100-fold over channels formed by the pore-forming KCNQ1 subunits alone, which effectively amplifies current because native PIP 2 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 PIP 2 sensitivity. Long QT syndrome associated mutations of this site lower PIP 2 affinity, resulting in reduced current. Application of exogenous PIP 2 to these mutants restores wild-type channel activity. These results reveal a vital role of PIP 2 for KCNE1 modulation of I Ks channels that may represent a common mechanism of auxiliary subunit modulation of many ion channels.