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J Biol Chem
2014 Aug 15;28933:22749-22758. doi: 10.1074/jbc.M114.589796.
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Novel Kv7.1-phosphatidylinositol 4,5-bisphosphate interaction sites uncovered by charge neutralization scanning.
Eckey K, Wrobel E, Strutz-Seebohm N, Pott L, Schmitt N, Seebohm G.
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Kv7.1 to Kv7.5 α-subunits belong to the family of voltage-gated potassium channels (Kv). Assembled with the β-subunit KCNE1, Kv7.1 conducts the slowly activating potassium current IKs, which is one of the major currents underlying repolarization of the cardiac action potential. A known regulator of Kv7 channels is the lipid phosphatidylinositol 4,5-bisphosphate (PIP2). PIP2 increases the macroscopic current amplitude by stabilizing the open conformation of 7.1/KCNE1 channels. However, knowledge about the exact nature of the interaction is incomplete. The aim of this study was the identification of the amino acids responsible for the interaction between Kv7.1 and PIP2. We generated 13 charge neutralizing point mutations at the intracellular membrane border and characterized them electrophysiologically in complex with KCNE1 under the influence of diC8-PIP2. Electrophysiological analysis of corresponding long QT syndrome mutants suggested impaired PIP2 regulation as the cause for channel dysfunction. To clarify the underlying structural mechanism of PIP2 binding, molecular dynamics simulations of Kv7.1/KCNE1 complexes containing two PIP2 molecules in each subunit at specific sites were performed. Here, we identified a subset of nine residues participating in the interaction of PIP2 and Kv7.1/KCNE1. These residues may form at least two binding pockets per subunit, leading to the stabilization of channel conformations upon PIP2 binding.
Angelo,
KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current.
2002, Pubmed,
Xenbase
Angelo,
KCNE5 induces time- and voltage-dependent modulation of the KCNQ1 current.
2002,
Pubmed
,
Xenbase Barhanin,
K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current.
1996,
Pubmed
,
Xenbase Berridge,
Inositol trisphosphate and diacylglycerol as second messengers.
1984,
Pubmed Chouabe,
Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk.
2000,
Pubmed Chuang,
Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition.
2001,
Pubmed
,
Xenbase Delmas,
Pathways modulating neural KCNQ/M (Kv7) potassium channels.
2005,
Pubmed Demolombe,
Differential expression of KvLQT1 and its regulator IsK in mouse epithelia.
2001,
Pubmed Donger,
KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome.
1997,
Pubmed Fan,
Anionic phospholipids activate ATP-sensitive potassium channels.
1997,
Pubmed FRASER,
GENETICAL ASPECTS OF THE CARDIO-AUDITORY SYNDROME OF JERVELL AND LANGE-NIELSEN (CONGENITAL DEAFNESS AND ELECTROCARDIOGRAPHIC ABNORMALITIES).
1964,
Pubmed Grunnet,
KCNE4 is an inhibitory subunit to the KCNQ1 channel.
2002,
Pubmed
,
Xenbase Hansen,
Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
2011,
Pubmed Hernandez,
A carboxy-terminal inter-helix linker as the site of phosphatidylinositol 4,5-bisphosphate action on Kv7 (M-type) K+ channels.
2008,
Pubmed Hilgemann,
The complex and intriguing lives of PIP2 with ion channels and transporters.
2001,
Pubmed Huang,
Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma.
1998,
Pubmed
,
Xenbase Huijbregts,
Lipid metabolism and regulation of membrane trafficking.
2000,
Pubmed JERVELL,
Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death.
1957,
Pubmed Jespersen,
The KCNQ1 potassium channel: from gene to physiological function.
2005,
Pubmed Kang,
Structure of KCNE1 and implications for how it modulates the KCNQ1 potassium channel.
2008,
Pubmed Kanovsky,
A new homozygous mutation of the KCNQ1 gene associated with both Romano-Ward and incomplete Jervell Lange-Nielsen syndromes in two sisters.
2010,
Pubmed Kapplinger,
Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test.
2009,
Pubmed Kubota,
Hypokalemia-induced long QT syndrome with an underlying novel missense mutation in S4-S5 linker of KCNQ1.
2000,
Pubmed Lopes,
Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies.
2002,
Pubmed
,
Xenbase Lopez,
A G Protein Mediates the Inhibition of the Voltage-Dependent Potassium M Current by Muscarine, LHRH, Substance P and UTP in Bullfrog Sympathetic Neurons.
1989,
Pubmed Loussouarn,
Phosphatidylinositol-4,5-bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage-gated potassium channels: a functional homology between voltage-gated and inward rectifier K+ channels.
2003,
Pubmed Martin,
PI(4,5)P(2) regulation of surface membrane traffic.
2001,
Pubmed Millat,
Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.
2006,
Pubmed Moss,
The long QT syndrome: a prospective international study.
1985,
Pubmed Moss,
The long QT syndrome. Prospective longitudinal study of 328 families.
1991,
Pubmed Napolitano,
Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice.
2005,
Pubmed Nebl,
Membrane cytoskeleton: PIP(2) pulls the strings.
2000,
Pubmed Nerbonne,
Molecular physiology of cardiac repolarization.
2005,
Pubmed Park,
Impaired KCNQ1-KCNE1 and phosphatidylinositol-4,5-bisphosphate interaction underlies the long QT syndrome.
2005,
Pubmed Pfaffinger,
Muscarine and t-LHRH suppress M-current by activating an IAP-insensitive G-protein.
1988,
Pubmed Pusch,
Increase of the single-channel conductance of KvLQT1 potassium channels induced by the association with minK.
1998,
Pubmed
,
Xenbase ROMANO,
[RARE CARDIAC ARRHYTHMIAS OF THE PEDIATRIC AGE. I. REPETITIVE PAROXYSMAL TACHYCARDIA].
1963,
Pubmed Sanguinetti,
Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel.
1996,
Pubmed
,
Xenbase Schroeder,
A constitutively open potassium channel formed by KCNQ1 and KCNE3.
2000,
Pubmed
,
Xenbase Sechi,
The actin cytoskeleton and plasma membrane connection: PtdIns(4,5)P(2) influences cytoskeletal protein activity at the plasma membrane.
2000,
Pubmed Seebohm,
Regulation of KCNQ4 potassium channel prepulse dependence and current amplitude by SGK1 in Xenopus oocytes.
2005,
Pubmed
,
Xenbase Seebohm,
Dependence of I(Ks) biophysical properties on the expression system.
2001,
Pubmed
,
Xenbase Seebohm,
Structural basis of PI(4,5)P2-dependent regulation of GluA1 by phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP5K2A).
2014,
Pubmed
,
Xenbase Selyanko,
Inhibition of KCNQ1-4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors.
2000,
Pubmed Shyng,
Structural determinants of PIP(2) regulation of inward rectifier K(ATP) channels.
2000,
Pubmed Strutz-Seebohm,
Structural basis of slow activation gating in the cardiac I Ks channel complex.
2011,
Pubmed
,
Xenbase Suh,
Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 4,5-bisphosphate synthesis.
2002,
Pubmed Tamargo,
Pharmacology of cardiac potassium channels.
2004,
Pubmed Thomas,
Characterization of a binding site for anionic phospholipids on KCNQ1.
2011,
Pubmed Thomas,
Differential phosphoinositide binding to components of the G protein-gated K+ channel.
2006,
Pubmed Tinel,
KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel.
2000,
Pubmed
,
Xenbase Tristani-Firouzi,
Voltage-dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits.
1998,
Pubmed
,
Xenbase WARD,
A NEW FAMILIAL CARDIAC SYNDROME IN CHILDREN.
1964,
Pubmed Whorton,
Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.
2011,
Pubmed
,
Xenbase Wrobel,
The KCNE Tango - How KCNE1 Interacts with Kv7.1.
2012,
Pubmed Xu,
KCNQ1 and KCNE1 in the IKs channel complex make state-dependent contacts in their extracellular domains.
2008,
Pubmed
,
Xenbase Yang,
Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome.
2009,
Pubmed Zaydman,
Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening.
2013,
Pubmed
,
Xenbase Zhang,
PIP(2) activates KCNQ channels, and its hydrolysis underlies receptor-mediated inhibition of M currents.
2003,
Pubmed
,
Xenbase Zhang,
Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions.
1999,
Pubmed
,
Xenbase
