Regulation of KCNQ/Kv7 family voltage-gated K+ channels by lipids.

Many years of studies have established that lipids can impact membrane protein structure and function through bulk membrane effects, by direct but transient annular interactions with the bilayer-exposed surface of protein transmembrane domains, and by specific binding to protein sites. Here, we focus on how phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function and how the structural details of the interactions of these lipids with ion channels are beginning to emerge. We focus on the Kv7 (KCNQ) subfamily of voltage-gated K+ channels, which are regulated by both PIP2 and PUFAs and play a variety of important roles in human health and disease. This article is part of a Special Issue entitled: Lipid order/lipid defects and lipid-control of protein activity edited by Dirk Schneider.

[1]  Ron O. Dror,et al.  Mechanism of Voltage Gating in Potassium Channels , 2012, Science.

[2]  Yongcheng Wang,et al.  The role of L1 loop in the mechanism of rhomboid intramembrane protease GlpG. , 2007, Journal of molecular biology.

[3]  B. Attali,et al.  The KCNQ1 (Kv7.1) COOH Terminus, a Multitiered Scaffold for Subunit Assembly and Protein Interaction* , 2008, Journal of Biological Chemistry.

[4]  F. Wieland,et al.  Specificity of intramembrane protein-lipid interactions. , 2011, Cold Spring Harbor perspectives in biology.

[5]  Linda M. Boland,et al.  Polyunsaturated Fatty Acid Modulation of Voltage-Gated Ion Channels , 2008, Cell Biochemistry and Biophysics.

[6]  J Robbins,et al.  KCNQ potassium channels: physiology, pathophysiology, and pharmacology. , 2001, Pharmacology & therapeutics.

[7]  B. Hille,et al.  Electrostatic Interaction of Internal Mg2+ with Membrane PIP2 Seen with KCNQ K+ Channels , 2007, The Journal of general physiology.

[8]  Zhe Lu,et al.  Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels , 2008, Nature.

[9]  Fredrik Elinder,et al.  An electrostatic potassium channel opener targeting the final voltage sensor transition , 2011, The Journal of general physiology.

[10]  Jeremiah D. Osteen,et al.  Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels , 2012, Proceedings of the National Academy of Sciences.

[11]  F. Charpentier,et al.  KCNE1–KCNQ1 osmoregulation by interaction of phosphatidylinositol‐4,5‐bisphosphate with Mg2+ and polyamines , 2010, The Journal of physiology.

[12]  Charles R. Sanders,et al.  The Amyloid Precursor Protein Has a Flexible Transmembrane Domain and Binds Cholesterol , 2012, Science.

[13]  M. Sanguinetti,et al.  Molecular Basis of Cardiac Delayed Rectifier Potassium Channel Function and Pharmacology. , 2016, Cardiac electrophysiology clinics.

[14]  H. Larsson,et al.  The KCNQ1 channel – remarkable flexibility in gating allows for functional versatility , 2015, The Journal of physiology.

[15]  Joseph E. Goose,et al.  MemProtMD: Automated Insertion of Membrane Protein Structures into Explicit Lipid Membranes , 2015, Structure.

[16]  M. Egret‐Charlier,et al.  A NMR study of the ionization of fatty acids, fatty amines and N-acylamino acids incorporated in phosphatidylcholine vesicles. , 1980, Biochimica et biophysica acta.

[17]  A. V. van Ginneken,et al.  Mutation in the KCNQ1 Gene Leading to the Short QT-Interval Syndrome , 2004, Circulation.

[18]  C. Sanders,et al.  Competition between homodimerization and cholesterol binding to the C99 domain of the amyloid precursor protein. , 2013, Biochemistry.

[19]  G. E. Atilla‐Gokcumen,et al.  Lipids in cell biology: how can we understand them better? , 2014, Molecular biology of the cell.

[20]  C. Robinson,et al.  A sliding selectivity scale for lipid binding to membrane proteins. , 2016, Current opinion in structural biology.

[21]  Pietro De Camilli,et al.  Phosphoinositides in cell regulation and membrane dynamics , 2006, Nature.

[22]  M. Takemoto,et al.  Regulation of membrane KCNQ1/KCNE1 channel density by sphingomyelin synthase 1. , 2016, American journal of physiology. Cell physiology.

[23]  Mark A. Zaydman,et al.  Kv7.1 ion channels require a lipid to couple voltage sensing to pore opening , 2013, Proceedings of the National Academy of Sciences.

[24]  David E. Clapham,et al.  A voltage-gated proton-selective channel lacking the pore domain , 2006, Nature.

[25]  F. Bezanilla,et al.  Resting state of the human proton channel dimer in a lipid bilayer , 2015, Proceedings of the National Academy of Sciences.

[26]  Tae-Joon Jeon,et al.  Transmembrane glycine zippers: physiological and pathological roles in membrane proteins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. V. Van Etten,et al.  The voltage-sensing domain of a phosphatase gates the pore of a potassium channel , 2013, The Journal of general physiology.

[28]  Seok-Yong Lee,et al.  Structure of the KvAP voltage-dependent K+ channel and its dependence on the lipid membrane , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[29]  A. Wilde,et al.  Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. , 2009, Heart rhythm.

[30]  R. Blunck,et al.  Mode shift of the voltage sensors in Shaker K+ channels is caused by energetic coupling to the pore domain , 2011, The Journal of general physiology.

[31]  R. MacKinnon,et al.  Phospholipids and the origin of cationic gating charges in voltage sensors , 2006, Nature.

[32]  C. Sanders,et al.  Purification and Structural Study of the Voltage-Sensor Domain of the Human KCNQ1 Potassium Ion Channel , 2014, Biochemistry.

[33]  Dan M Roden,et al.  Cardiac potassium channel dysfunction in sudden infant death syndrome. , 2007, Journal of molecular and cellular cardiology.

[34]  D. Hilgemann,et al.  Regulation of Cardiac Na+,Ca2+ Exchange and KATP Potassium Channels by PIP2 , 1996, Science.

[35]  G. Loussouarn,et al.  Opposite Effects of the S4–S5 Linker and PIP2 on Voltage-Gated Channel Function: KCNQ1/KCNE1 and Other Channels , 2012, Front. Pharmacol..

[36]  E. Campbell,et al.  Crystal Structure of a Mammalian Voltage-Dependent Shaker Family K+ Channel , 2005, Science.

[37]  T. Allen,et al.  The determinants of hydrophobic mismatch response for transmembrane helices. , 2013, Biochimica et biophysica acta.

[38]  G. Abbott,et al.  The Role of S4 Charges in Voltage-dependent and Voltage-independent KCNQ1 Potassium Channel Complexes , 2007, The Journal of general physiology.

[39]  S. Ferroni,et al.  Structural Compatibility between the Putative Voltage Sensor of Voltage-gated K+ Channels and the Prokaryotic KcsA Channel* , 2001, The Journal of Biological Chemistry.

[40]  T. Jentsch Neuronal KCNQ potassium channels:physislogy and role in disease , 2000, Nature Reviews Neuroscience.

[41]  Martin Lepšík,et al.  Substrate binding and specificity of rhomboid intramembrane protease revealed by substrate–peptide complex structures , 2014, The EMBO journal.

[42]  D. Marsh,et al.  Structure, dynamics and composition of the lipid-protein interface. Perspectives from spin-labelling. , 1998, Biochimica et biophysica acta.

[43]  D. Hilgemann,et al.  Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ , 1998, Nature.

[44]  R. Koeppe,et al.  Helical distortion in tryptophan- and lysine-anchored membrane-spanning alpha-helices as a function of hydrophobic mismatch: a solid-state deuterium NMR investigation using the geometric analysis of labeled alanines method. , 2008, Biophysical journal.

[45]  Maarten H. P. Kole,et al.  Heteromeric Kv7.2/7.3 Channels Differentially Regulate Action Potential Initiation and Conduction in Neocortical Myelinated Axons , 2014, The Journal of Neuroscience.

[46]  Jia-Bin Sun,et al.  Effects of unsaturated fatty acids on calcium-activated potassium current in gastric myocytes of guinea pigs. , 2005, World journal of gastroenterology.

[47]  T. Balla,et al.  Phosphoinositides: tiny lipids with giant impact on cell regulation. , 2013, Physiological reviews.

[48]  J. Trimmer,et al.  Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels , 2011, Pflügers Archiv - European Journal of Physiology.

[49]  Z. Molnár,et al.  Specificity of activation by phosphoinositides determines lipid regulation of Kir channels , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[50]  O. Pongs,et al.  Coupling of Voltage-Sensors to the Channel Pore: A Comparative View , 2012, Front. Pharmacol..

[51]  D. Roden,et al.  A Structural Requirement for Processing the Cardiac K+ Channel KCNQ1* , 2004, Journal of Biological Chemistry.

[52]  B S Brown,et al.  KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. , 1998, Science.

[53]  Yasushi Okamura,et al.  Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor , 2005, Nature.

[54]  K. Schulten,et al.  An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations , 2012, The Journal of general physiology.

[55]  Charles R Sanders,et al.  Cholesterol as a co‐solvent and a ligand for membrane proteins , 2014, Protein science : a publication of the Protein Society.

[56]  C. Romano CONGENITAL CARDIAC ARRHYTHMIA. , 1965, Lancet.

[57]  D. Jump The Biochemistry of n-3 Polyunsaturated Fatty Acids* 210 , 2002, The Journal of Biological Chemistry.

[58]  Alison M. Thomas,et al.  Characterization of a Binding Site for Anionic Phospholipids on KCNQ1* , 2010, The Journal of Biological Chemistry.

[59]  Kathleen F. Mittendorf,et al.  Impact of Bilayer Lipid Composition on the Structure and Topology of the Transmembrane Amyloid Precursor C99 Protein , 2014, Journal of the American Chemical Society.

[60]  Yasushi Okamura,et al.  A Voltage Sensor-Domain Protein Is a Voltage-Gated Proton Channel , 2006, Science.

[61]  S. Petrou,et al.  Fatty acid augmentation of the cardiac slowly activating delayed rectifier current (IKs) is conferred by hminK , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[62]  B. Hille,et al.  Phosphoinositides regulate ion channels. , 2015, Biochimica et biophysica acta.

[63]  D. A. Brown,et al.  Inhibition of KCNQ1‐4 potassium channels expressed in mammalian cells via M1 muscarinic acetylcholine receptors , 2000, The Journal of physiology.

[64]  David L. Worcester,et al.  Structure and hydration of membranes embedded with voltage-sensing domains , 2009, Nature.

[65]  Matthias Stein,et al.  The Molecular Basis of Polyunsaturated Fatty Acid Interactions with the Shaker Voltage-Gated Potassium Channel , 2016, PLoS Comput. Biol..

[66]  Fredrik Elinder,et al.  Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids. , 2008, Biophysical journal.

[67]  N. Goto,et al.  Influence of hydrophobic mismatch on the catalytic activity of Escherichia coli GlpG rhomboid protease , 2015, Protein science : a publication of the Protein Society.

[68]  B. Hille,et al.  Regulation of voltage-gated potassium channels by PI(4,5)P2 , 2012, The Journal of general physiology.

[69]  Roderick MacKinnon,et al.  Solution structure and phospholipid interactions of the isolated voltage-sensor domain from KvAP. , 2010, Journal of molecular biology.

[70]  M. Gollob,et al.  Voltage-Gated Sodium Channels: Biophysics, Pharmacology, and Related Channelopathies , 2012, Front. Pharmacol..

[71]  Douglas J. Tobias,et al.  Voltage Sensing in Membranes: From Macroscopic Currents to Molecular Motions , 2015, The Journal of Membrane Biology.

[72]  Ward Oc A NEW FAMILIAL CARDIAC SYNDROME IN CHILDREN. , 1964 .

[73]  C. Sanders,et al.  Structural models for the KCNQ1 voltage-gated potassium channel. , 2007, Biochemistry.

[74]  R. Stroud,et al.  Structure, inhibition, and regulatory sites of TPC1 from Arabidopsis thaliana , 2016, Nature.

[75]  Youxing Jiang,et al.  Structure of Voltage-gated Two-pore Channel TPC1 from Arabidopsis thaliana , 2015, Nature.

[76]  C. Petit,et al.  KCNQ4, a K+ channel mutated in a form of dominant deafness, is expressed in the inner ear and the central auditory pathway. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[77]  W. Catterall,et al.  The VGL-Chanome: A Protein Superfamily Specialized for Electrical Signaling and Ionic Homeostasis , 2004, Science's STKE.

[78]  Wei Huang,et al.  KCNQ1 Gain-of-Function Mutation in Familial Atrial Fibrillation , 2003, Science.

[79]  C. Robinson,et al.  Probing the Lipid Annular Belt by Gas‐Phase Dissociation of Membrane Proteins in Nanodiscs , 2015, Angewandte Chemie.

[80]  Diomedes E Logothetis,et al.  PIP2 Activates KCNQ Channels, and Its Hydrolysis Underlies Receptor-Mediated Inhibition of M Currents , 2003, Neuron.

[81]  Meng Cui,et al.  PIP2 controls voltage-sensor movement and pore opening of Kv channels through the S4–S5 linker , 2012, Proceedings of the National Academy of Sciences.

[82]  Annick Thomas,et al.  A Long QT Mutation Substitutes Cholesterol for Phosphatidylinositol-4,5-Bisphosphate in KCNQ1 Channel Regulation , 2014, PloS one.

[83]  Lydia Josephs,et al.  Localization and proteomic characterization of cholesterol-rich membrane microdomains in the inner ear. , 2014, Journal of proteomics.

[84]  Coeli M B Lopes,et al.  PKA and PKC partially rescue Long QT type 1 phenotype by restoring channel-PIP2 interactions , 2010, Channels.

[85]  Jacques Barhanin,et al.  KvLQT1 and IsK (minK) proteins associate to form the IKS cardiac potassium current , 1996, Nature.

[86]  G. von Heijne,et al.  Interface connections of a transmembrane voltage sensor. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[87]  Anthony G. Lee Annular events: lipid-protein interactions , 1977 .

[88]  L. Pott,et al.  Novel Kv7.1-Phosphatidylinositol 4,5-Bisphosphate Interaction Sites Uncovered by Charge Neutralization Scanning* , 2014, The Journal of Biological Chemistry.

[89]  Donald Voet,et al.  Fundamentals of Biochemistry , 1999 .

[90]  Diomedes E. Logothetis,et al.  Channelopathies linked to plasma membrane phosphoinositides , 2010, Pflügers Archiv - European Journal of Physiology.

[91]  Yu Huang,et al.  Electrostatic interactions of S4 voltage sensor in shaker K+ channel , 1995, Neuron.

[92]  Kathleen F. Mittendorf,et al.  Tolerance to changes in membrane lipid composition as a selected trait of membrane proteins. , 2011, Biochemistry.

[93]  M. Sanguinetti,et al.  Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKS potassium channel , 1996, Nature.

[94]  M. Sansom,et al.  Kv Channel Gating Requires a Compatible S4-S5 Linker and Bottom Part of S6, Constrained by Non-interacting Residues , 2008, The Journal of general physiology.

[95]  D. Brown,et al.  PIP2-dependent inhibition of M-type (Kv7.2/7.3) potassium channels: direct on-line assessment of PIP2 depletion by Gq-coupled receptors in single living neurons , 2007, Pflügers Archiv - European Journal of Physiology.

[96]  Maria Dahlin,et al.  Polyunsaturated fatty acids and cerebrospinal fluid from children on the ketogenic diet open a voltage-gated K channel: A putative mechanism of antiseizure action , 2008, Epilepsy Research.

[97]  P. Coumel,et al.  A novel mutation in the potassium channel gene KVLQT1 causes the Jervell and Lange-Nielsen cardioauditory syndrome , 1997, Nature Genetics.

[98]  S. Harrison,et al.  Lipid–protein interactions in double-layered two-dimensional AQP0 crystals , 2005, Nature.

[99]  Xiao Tao,et al.  Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2 , 2011, Nature.

[100]  Yang Li,et al.  Migration of PIP2 lipids on voltage-gated potassium channel surface influences channel deactivation , 2015, Scientific Reports.

[101]  E. Campbell,et al.  Voltage Sensor of Kv1.2: Structural Basis of Electromechanical Coupling , 2005, Science.

[102]  A. A. Alabi,et al.  Portability of paddle motif function and pharmacology in voltage sensors , 2007, Nature.

[103]  R. MacKinnon,et al.  X-ray structure of the mammalian GIRK2 – βγ G protein complex , 2013, Nature.

[104]  Anthony G Lee,et al.  How lipids affect the activities of integral membrane proteins. , 2004, Biochimica et biophysica acta.

[105]  Olaf S Andersen,et al.  Bilayer thickness and membrane protein function: an energetic perspective. , 2007, Annual review of biophysics and biomolecular structure.

[106]  Christopher Miller,et al.  Functional Reconstitution of a Prokaryotic K+ Channel , 1998, The Journal of general physiology.

[107]  E. Tajkhorshid,et al.  Atomic-level description of protein-lipid interactions using an accelerated membrane model. , 2016, Biochimica et biophysica acta.

[108]  D. Papazian,et al.  Electrostatic interactions between transmembrane segments mediate folding of Shaker K+ channel subunits. , 1997, Biophysical journal.

[109]  Klaus Schulten,et al.  Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain , 2013, Nature Structural &Molecular Biology.

[110]  A. Shaytan,et al.  Voltage-gated ion channel modulation by lipids: insights from molecular dynamics simulations. , 2014, Biochimica et biophysica acta.

[111]  Hualiang Jiang,et al.  Dynamic PIP2 interactions with voltage sensor elements contribute to KCNQ2 channel gating , 2013, Proceedings of the National Academy of Sciences.

[112]  Bruno Beaumelle,et al.  HIV-Tat induces a decrease in IKr and IKsvia reduction in phosphatidylinositol-(4,5)-bisphosphate availability. , 2016, Journal of molecular and cellular cardiology.

[113]  M. Klein,et al.  Evolutionary imprint of activation: The design principles of VSDs , 2014, The Journal of general physiology.

[114]  A. Arseniev,et al.  NMR structural and dynamical investigation of the isolated voltage-sensing domain of the potassium channel KvAP: implications for voltage gating. , 2010, Journal of the American Chemical Society.

[115]  I. Levental,et al.  Structural determinants of protein partitioning into ordered membrane domains and lipid rafts. , 2015, Chemistry and physics of lipids.

[116]  E. Sherr,et al.  Epileptic Encephalopathies: New Genes and New Pathways , 2014, Neurotherapeutics.

[117]  Mark A. Zaydman,et al.  KCNE1 enhances phosphatidylinositol 4,5-bisphosphate (PIP2) sensitivity of IKs to modulate channel activity , 2011, Proceedings of the National Academy of Sciences.

[118]  Kyu-Ho Park,et al.  Impaired KCNQ1–KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome , 2005, Circulation research.

[119]  Laura Solé,et al.  Impact of KCNE subunits on KCNQ1 (Kv7.1) channel membrane surface targeting , 2010, Journal of cellular physiology.

[120]  D. Escande,et al.  Phosphatidylinositol‐4,5‐bisphosphate, PIP2, controls KCNQ1/KCNE1 voltage‐gated potassium channels: a functional homology between voltage‐gated and inward rectifier K+ channels , 2003, The EMBO journal.

[121]  S. Hansen Lipid agonism: The PIP2 paradigm of ligand-gated ion channels. , 2015, Biochimica et biophysica acta.

[122]  D. Hilgemann,et al.  The Complex and Intriguing Lives of PIP2 with Ion Channels and Transporters , 2001, Science's STKE.

[123]  B. Hille,et al.  Recovery from Muscarinic Modulation of M Current Channels Requires Phosphatidylinositol 4,5-Bisphosphate Synthesis , 2002, Neuron.

[124]  J. Killian,et al.  How protein transmembrane segments sense the lipid environment. , 2007, Biochemistry.

[125]  B Attali,et al.  A recessive C‐terminal Jervell and Lange‐Nielsen mutation of the KCNQ1 channel impairs subunit assembly , 2000, The EMBO journal.

[126]  Zhe Lu,et al.  Ion conduction pore is conserved among potassium channels , 2001, Nature.

[127]  Carola Hunte,et al.  Lipids in membrane protein structures. , 2004, Biochimica et biophysica acta.

[128]  H. Tsao,et al.  Denaturing high-performance liquid chromatography screening of the long QT syndrome-related cardiac sodium and potassium channel genes and identification of novel mutations and single nucleotide polymorphisms , 2005, Journal of Human Genetics.

[129]  O. Pongs,et al.  Ancillary subunits associated with voltage-dependent K+ channels. , 2010, Physiological reviews.

[130]  P. Yeagle,et al.  Non-covalent binding of membrane lipids to membrane proteins. , 2014, Biochimica et biophysica acta.

[131]  F. Bezanilla How membrane proteins sense voltage , 2008, Nature Reviews Molecular Cell Biology.

[132]  D. Marsh,et al.  ESR determination of lipid translational diffusion coefficients at low spin-label concentrations in biological membranes, using exchange broadening, exchange narrowing, and dipole-dipole interactions , 1987 .

[133]  K. Sawada,et al.  Chronic Probucol Treatment Decreases the Slow Component of the Delayed-Rectifier Potassium Current in CHO Cells Transfected With KCNQ1 and KCNE1: A Novel Mechanism of QT Prolongation , 2012, Journal of cardiovascular pharmacology.

[134]  E. Campbell,et al.  Atomic structure of a voltage-dependent K+ channel in a lipid membrane-like environment , 2007, Nature.

[135]  K. Sawada,et al.  Probucol and the cholesterol synthesis inhibitors simvastatin and triparanol regulate I ks channel function differently , 2013, Human & experimental toxicology.

[136]  R. MacKinnon,et al.  Chemistry of ion coordination and hydration revealed by a K+ channel–Fab complex at 2.0 Å resolution , 2001, Nature.

[137]  S. White,et al.  Rhomboid protease dynamics and lipid interactions. , 2009, Structure.

[138]  G. E. Atilla‐Gokcumen,et al.  Dividing Cells Regulate Their Lipid Composition and Localization , 2014, Cell.

[139]  Yang Li,et al.  Regulation of Kv7 (KCNQ) K+ Channel Open Probability by Phosphatidylinositol 4,5-Bisphosphate , 2005, The Journal of Neuroscience.

[140]  D. Minor,et al.  Crystal structure of a trimeric form of the KV7.1 (KCNQ1) A‐domain tail coiled‐coil reveals structural plasticity and context dependent changes in a putative coiled‐coil trimerization motif , 2009, Protein science : a publication of the Protein Society.

[141]  M. Taglialatela,et al.  Driving with no brakes: molecular pathophysiology of Kv7 potassium channels. , 2011, Physiology.

[142]  M. Sansom,et al.  Anionic phospholipid interactions with the potassium channel KcsA: simulation studies. , 2006, Biophysical journal.

[143]  F. Barrantes Phylogenetic conservation of protein-lipid motifs in pentameric ligand-gated ion channels. , 2015, Biochimica et biophysica acta.

[144]  J. Cui Voltage-Dependent Gating: Novel Insights from KCNQ1 Channels. , 2016, Biophysical journal.

[145]  T. Morrow,et al.  Early Painful Diabetic Neuropathy Is Associated with Differential Changes in Tetrodotoxin-sensitive and -resistant Sodium Channels in Dorsal Root Ganglion Neurons in the Rat* , 2004, Journal of Biological Chemistry.

[146]  K. Sunagawa,et al.  Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil. , 2005, Journal of the American College of Cardiology.

[147]  R. MacKinnon,et al.  Lipids in the structure, folding, and function of the KcsA K+ channel. , 2002, Biochemistry.

[148]  M. Klein,et al.  Free-energy landscape of ion-channel voltage-sensor–domain activation , 2014, Proceedings of the National Academy of Sciences of the United States of America.

[149]  Roderick MacKinnon,et al.  Crystal Structure of the Mammalian GIRK2 K+ Channel and Gating Regulation by G Proteins, PIP2, and Sodium , 2011, Cell.

[150]  G. Abbott Biology of the KCNQ1 Potassium Channel , 2014 .

[151]  M. D. de Planque,et al.  Probing the interaction of lipids with the non-annular binding sites of the potassium channel KcsA by magic-angle spinning NMR , 2012, Biochimica et biophysica acta.

[152]  C. Kubisch,et al.  Moderate loss of function of cyclic-AMP-modulated KCNQ2/KCNQ3 K+ channels causes epilepsy , 1998, Nature.

[153]  D. A. Brown,et al.  Molecular correlates of the M‐current in cultured rat hippocampal neurons , 2002, The Journal of physiology.

[154]  M. Cadene,et al.  X-ray structure of a voltage-dependent K+ channel , 2003, Nature.

[155]  C. Robinson,et al.  Different modes of lipid binding to membrane proteins probed by mass spectrometry. , 2015, Journal of the American Chemical Society.

[156]  W. R. Kobertz,et al.  KCNE Peptides Differently Affect Voltage Sensor Equilibrium and Equilibration Rates in KCNQ1 K+ Channels , 2008, The Journal of general physiology.

[157]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[158]  Fredrik Elinder,et al.  Electrostatic tuning of cellular excitability. , 2010, Biophysical journal.

[159]  O. Pongs,et al.  Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt IKS regulation by PKA and PIP2 , 2014, Journal of Cell Science.

[160]  S. Berkovic,et al.  A potassium channel mutation in neonatal human epilepsy. , 1998, Science.

[161]  A. Jervell,et al.  Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval, and sudden death , 1957 .

[162]  Fredrik Elinder,et al.  Polyunsaturated fatty acid analogs act antiarrhythmically on the cardiac IKs channel , 2015, Proceedings of the National Academy of Sciences.

[163]  J. East,et al.  Interactions of phospholipids with the potassium channel KcsA. , 2002, Biophysical journal.

[164]  F. Charpentier,et al.  Phosphatidylinositol-4,5-bisphosphate (PIP(2)) stabilizes the open pore conformation of the Kv11.1 (hERG) channel. , 2010, Biophysical journal.

[165]  Michael Christiansen,et al.  The genetic basis of long QT and short QT syndromes: A mutation update , 2009, Human mutation.

[166]  Jianmin Cui,et al.  PIP2-dependent coupling is prominent in Kv7.1 due to weakened interactions between S4-S5 and S6 , 2015, Scientific Reports.

[167]  L. Qin,et al.  Conserved lipid-binding sites in membrane proteins: a focus on cytochrome c oxidase. , 2007, Current opinion in structural biology.

[168]  S. Severi,et al.  Marine n-3 PUFAs modulate IKs gating, channel expression, and location in membrane microdomains. , 2015, Cardiovascular research.

[169]  P. Marius,et al.  The interfacial lipid binding site on the potassium channel KcsA is specific for anionic phospholipids. , 2005, Biophysical journal.