Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Biol Chem
2014 Aug 15;28933:22749-22758. doi: 10.1074/jbc.M114.589796.
Show Gene links
Show Anatomy links
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
.
???displayArticle.abstract???
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
