title: KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St Louis, MO 63130, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.forename: Mark A
authors.initials: MA
authors.lastname: Zaydman
authors.forename: Dick
authors.initials: D
authors.lastname: Wu
authors.forename: Jingyi
authors.initials: J
authors.lastname: Shi
authors.forename: Michael
authors.initials: M
authors.lastname: Guan
authors.forename: Brett
authors.initials: B
authors.lastname: Virgin-Downey
authors.forename: Jianmin
authors.initials: J
authors.lastname: Cui
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D006801:Humans; D007477:Ions; D051657:KCNQ1 Potassium Channel / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry; D008133:Long QT Syndrome / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D018408:Patch-Clamp Techniques; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D015221:Potassium Channels / Q000737:chemistry; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D029867:Xenopus Proteins / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D007477:Ions; C530745:KCNE1 protein, Xenopus; C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D008055:Lipids; D019269:Phosphatidylinositol 4,5-Diphosphate; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D029867:Xenopus Proteins