KCNQ potassium channels: physiology, pathophysiology, and pharmacology.

KCNQ genes encode a growing family of six transmembrane domains, single pore-loop, K(+) channel alpha-subunits that have a wide range of physiological correlates. KCNQ1 (KvLTQ1) is co-assembled with the product of the KCNE1 (minimal K(+)-channel protein) gene in the heart to form a cardiac-delayed rectifier-like K(+) current. Mutations in this channel can cause one form of inherited long QT syndrome (LQT1), as well as being associated with a form of deafness. KCNQ1 can also co-assemble with KCNE3, and may be the molecular correlate of the cyclic AMP-regulated K(+) current present in colonic crypt cells. KCNQ2 and KCNQ3 heteromultimers are thought to underlie the M-current; mutations in these genes may cause an inherited form of juvenile epilepsy. The KCNQ4 gene is thought to encode the molecular correlate of the I(K,n) in outer hair cells of the cochlea and I(K,L) in Type I hair cells of the vestibular apparatus, mutations in which lead to a form of inherited deafness. The recently identified KCNQ5 gene is expressed in brain and skeletal muscle, and can co-assemble with KCNQ3, suggesting it may also play a role in the M-current heterogeneity. This review will set this family of K(+) channels amongst the other known families. It will highlight the genes, physiology, pharmacology, and pathophysiology of this recently discovered, but important, family of K(+) channels.

[1]  L. Salkoff,et al.  Eight Potassium Channel Families Revealed by the C. elegans Genome Project , 1996, Neuropharmacology.

[2]  R. MacKinnon,et al.  The aromatic binding site for tetraethylammonium ion on potassium channels , 1992, Neuron.

[3]  L. Toro,et al.  Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[4]  B. Robertson,et al.  A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Y. Jan,et al.  Voltage‐gated and inwardly rectifying potassium channels , 1997, The Journal of physiology.

[6]  C. Kros,et al.  Developmental expression of the potassium current IK,n contributes to maturation of mouse outer hair cells , 1999, The Journal of physiology.

[7]  B. S. Brown,et al.  Selectivity of linopirdine (DuP 996), a neurotransmitter release enhancer, in blocking voltage-dependent and calcium-activated potassium currents in hippocampal neurons. , 1998, The Journal of pharmacology and experimental therapeutics.

[8]  A. Mitsudome,et al.  A novel mutation of KCNQ3 (c.925T→C) in a Japanese family with benign familial neonatal convulsions , 2000, Annals of neurology.

[9]  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.

[10]  O. Pongs,et al.  Voltage‐gated potassium channels: from hyperexcitability to excitement , 1999, FEBS letters.

[11]  T. Jegla,et al.  Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. , 2000, Molecular pharmacology.

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

[13]  D. A. Brown,et al.  Kinetic and pharmacological properties of the M‐current in rodent neuroblastoma x glioma hybrid cells. , 1992, The Journal of physiology.

[14]  K. Wang,et al.  Cloning and functional expression of rKCNQ2 K(+) channel from rat brain. , 2000, Brain research. Molecular brain research.

[15]  J. Benhorin,et al.  Images in clinical medicine. Congenital long-QT syndrome. , 1997, The New England journal of medicine.

[16]  Kortaro Tanaka,et al.  Disruption of the Epilepsy KCNQ2 Gene Results in Neural Hyperexcitability , 2000, Journal of neurochemistry.

[17]  J. Robbins,et al.  The role of ryanodine receptors in the cyclic ADP ribose modulation of the M‐like current in rodent m1 muscarinic receptor‐transformed NG108‐15 cells , 1999, The Journal of physiology.

[18]  H. Guy,et al.  The S. cerevisiae outwardly-rectifying potassium channel (DUK1) identifies a new family of channels with duplicated pore domains. , 1996, Receptors & channels.

[19]  R. Netzer,et al.  The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits , 2000, Neuroscience Letters.

[20]  J. Inazawa,et al.  Reconstitution of IKATP: An Inward Rectifier Subunit Plus the Sulfonylurea Receptor , 1995, Science.

[21]  M. Keating,et al.  Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. , 1998, Genomics.

[22]  M. Lazdunski,et al.  TWIK‐1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. , 1996, The EMBO journal.

[23]  S. Viskin Long QT syndromes and torsade de pointes , 1999, The Lancet.

[24]  Robin J. Leach,et al.  A pore mutation in a novel KQT-like potassium channel gene in an idiopathic epilepsy family , 1998, Nature Genetics.

[25]  O. Andreassen,et al.  Mice Deficient in Cellular Glutathione Peroxidase Show Increased Vulnerability to Malonate, 3-Nitropropionic Acid, and 1-Methyl-4-Phenyl-1,2,5,6-Tetrahydropyridine , 2000, The Journal of Neuroscience.

[26]  M. Okada,et al.  Dysfunction of M-channel enhances propagation of neuronal excitability in rat hippocampus monitored by multielectrode dish and microdialysis systems , 2000, Neuroscience Letters.

[27]  L. Kaczmarek,et al.  Properties and regulation of the minK potassium channel protein. , 1997, Physiological reviews.

[28]  M. Lazdunski,et al.  A pH-sensitive Yeast Outward Rectifier K Channel with Two Pore Domains and Novel Gating Properties (*) , 1996, The Journal of Biological Chemistry.

[29]  D. A. Brown,et al.  M‐currents and other potassium currents in bullfrog sympathetic neurones , 1982, The Journal of physiology.

[30]  M. Blatt,et al.  Mutations in the pore regions of the yeast K+ channel YKC1 affect gating by extracellular K+ , 1998, The EMBO journal.

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

[32]  F Bezanilla,et al.  The voltage sensor in voltage-dependent ion channels. , 2000, Physiological reviews.

[33]  S. Goldstein,et al.  The conduction pore of a cardiac potassium channel , 1998, Nature.

[34]  B. Attali,et al.  Stilbenes and fenamates rescue the loss of IKS channel function induced by an LQT5 mutation and other IsK mutants , 1999, The EMBO journal.

[35]  M. Schwake,et al.  Surface Expression and Single Channel Properties of KCNQ2/KCNQ3, M-type K+ Channels Involved in Epilepsy* , 2000, The Journal of Biological Chemistry.

[36]  J F Ashmore,et al.  Ionic currents of outer hair cells isolated from the guinea‐pig cochlea. , 1992, The Journal of physiology.

[37]  M. Sanguinetti,et al.  Voltage‐dependent inactivation of the human K+ channel KvLQT1 is eliminated by association with minimal K+ channel (minK) subunits , 1998, The Journal of physiology.

[38]  A. Wei,et al.  Molecular Cloning and Functional Expression of KCNQ5, a Potassium Channel Subunit That May Contribute to Neuronal M-current Diversity* , 2000, The Journal of Biological Chemistry.

[39]  D. A. Brown,et al.  On the mechanism of M‐current inhibition by muscarinic m1 receptors in DNA‐transfected rodent neuroblastoma x glioma cells. , 1993, The Journal of physiology.

[40]  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.

[41]  B. Robertson The real life of voltage-gated K+ channels: more than model behaviour. , 1997, Trends in pharmacological sciences.

[42]  M. Blanar,et al.  Functional Expression of Two KvLQT1-related Potassium Channels Responsible for an Inherited Idiopathic Epilepsy* , 1998, The Journal of Biological Chemistry.

[43]  M. Leppert,et al.  Benign familial neonatal convulsions linked to genetic markers on chromosome 20 , 1989, Nature.

[44]  F. Sesti,et al.  A Molecular Target for Viral Killer Toxin TOK1 Potassium Channels , 1999, Cell.

[45]  R. MacKinnon Determination of the subunit stoichiometry of a voltage-activated potassium channel , 1991, Nature.

[46]  Thomas J. Jentsch,et al.  KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents* , 2000, The Journal of Biological Chemistry.

[47]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[48]  Andre Terzic,et al.  Channelopathies of inwardly rectifying potassium channels , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[49]  O. Pongs,et al.  A physiological role for ether-à-go-go K+ channels? , 1997, Trends in Neurosciences.

[50]  W. Edwards,et al.  Molecular diagnosis of the inherited long-QT syndrome in a woman who died after near-drowning. , 1999, The New England journal of medicine.

[51]  F Mammano,et al.  Differential expression of outer hair cell potassium currents in the isolated cochlea of the guinea‐pig. , 1996, The Journal of physiology.

[52]  D. A. Brown,et al.  Effects of a Cognition‐enhancer, Linopirdine (DuP 996), on M‐type Potassium Currents (IK(M)) Some Other Voltage‐ and Ligand‐gated Membrane Currents in Rat Sympathetic Neurons , 1997, The European journal of neuroscience.

[53]  D. A. Brown,et al.  Coupling of Muscarinic Receptor Subtypes to Ion Channels: Experiments on Neuroblastoma Hybrid Cells a , 1993, Annals of the New York Academy of Sciences.

[54]  M. Berger,et al.  Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Thomas Friedrich,et al.  KCNQ4, a Novel Potassium Channel Expressed in Sensory Outer Hair Cells, Is Mutated in Dominant Deafness , 1999, Cell.

[56]  H. Lester,et al.  Gain of function mutants: ion channels and G protein-coupled receptors. , 2000, Annual review of neuroscience.

[57]  K. Starke,et al.  M‐type K+ currents in rat cultured thoracolumbar sympathetic neurones and their role in uracil nucleotide‐evoked noradrenaline release , 2000, British journal of pharmacology.

[58]  M. Lazdunski,et al.  The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3 , 1998, FEBS letters.

[59]  P. Fuchs,et al.  A molecular mechanism for electrical tuning of cochlear hair cells. , 1999, Science.

[60]  S. Burbidge,et al.  Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. , 2000, Molecular pharmacology.

[61]  D. A. Brown,et al.  Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone , 1980, Nature.

[62]  S. Priori,et al.  Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. , 1999, Circulation.

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

[64]  D. Snyders,et al.  Structure and function of cardiac potassium channels. , 1999, Cardiovascular research.

[65]  D. A. Brown,et al.  Two Types of K+ Channel Subunit, Erg1 and KCNQ2/3, Contribute to the M-Like Current in a Mammalian Neuronal Cell , 1999, The Journal of Neuroscience.

[66]  Miguel Salinas,et al.  Cloning and Expression of a Novel pH-sensitive Two Pore Domain K+ Channel from Human Kidney* , 1998, The Journal of Biological Chemistry.

[67]  D. A. Brown,et al.  On the transduction mechanism for muscarine‐induced inhibition of M‐current in cultured rat sympathetic neurones. , 1989, The Journal of physiology.

[68]  B. S. Brown,et al.  Reduction of spike frequency adaptation and blockade of M‐current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer , 1995, British journal of pharmacology.

[69]  D. A. Brown,et al.  M-currents in voltage-clamped mammalian sympathetic neurones , 1981, Neuroscience Letters.

[70]  D. J. Driscoll,et al.  A maternally methylated CpG island in KvLQT1 is associated with an antisense paternal transcript and loss of imprinting in Beckwith-Wiedemann syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[71]  S. Waldegger,et al.  A constitutively open potassium channel formed by KCNQ1 and KCNE3 , 2000, Nature.

[72]  M. Lazdunski,et al.  M‐type KCNQ2–KCNQ3 potassium channels are modulated by the KCNE2 subunit , 2000, FEBS letters.

[73]  L. Jan,et al.  Ion channel genes and human neurological disease: recent progress, prospects, and challenges. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[74]  N. Marrion,et al.  Control of M-current. , 1997, Annual review of physiology.

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

[76]  B. S. Brown,et al.  Inhibition of M-current in cultured rat superior cervical ganglia by linopirdine: Mechanism of action studies , 1997, Neuropharmacology.

[77]  O. Pongs,et al.  Inactivation properties of voltage-gated K+ channels altered by presence of β-subunit , 1994, Nature.

[78]  M. Lazdunski,et al.  Properties of KvLQT1 K+ channel mutations in Romano–Ward and Jervell and Lange‐Nielsen inherited cardiac arrhythmias , 1997, The EMBO journal.

[79]  R. Earl,et al.  Two new potent neurotransmitter release enhancers, 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone and 10,10-bis(2-fluoro-4-pyridinylmethyl)-9(10H)-anthracenone: comparison to linopirdine. , 1998, The Journal of pharmacology and experimental therapeutics.

[80]  D. A. Brown,et al.  Putative M-type potassium channels in neuroblastoma-glioma hybrid cells: inhibition by muscarine and bradykinin. , 1995, Receptors & channels.

[81]  L. Salkoff,et al.  Surfing the DNA databases for K+ channels nets yet more diversity , 1995, Neuron.

[82]  F. Ashcroft Ion channels and disease , 1999, Oxford Textbook of Medicine.

[83]  Leonard K. Kaczmarek,et al.  A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem , 1995, Nature.

[84]  W. Stühmer,et al.  The role of the IsK protein in the specific pharmacological properties of the IKs channel complex , 1997, British journal of pharmacology.

[85]  D. Mckinnon,et al.  Molecular basis for differential sensitivity of KCNQ and I(Ks) channels to the cognitive enhancer XE991. , 2000, Molecular pharmacology.

[86]  J. Nerbonne Molecular basis of functional voltage‐gated K+ channel diversity in the mammalian myocardium , 2000, The Journal of physiology.

[87]  R. Eatock,et al.  Major potassium conductance in type I hair cells from rat semicircular canals: characterization and modulation by nitric oxide. , 2000, Journal of neurophysiology.

[88]  A. Feinberg,et al.  Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith-Wiedemann syndrome and is independent of insulin-like growth factor II imprinting. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[89]  D. A. Brown,et al.  Differential tetraethylammonium sensitivity of KCNQ1–4 potassium channels , 2000, British journal of pharmacology.

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

[91]  G Van Camp,et al.  Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families. , 1999, Human molecular genetics.

[92]  M. Patton,et al.  Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts. , 1999, Circulation.

[93]  J. Schwarz,et al.  Separation of M‐like current and ERG current in NG108‐15 cells , 1999, British journal of pharmacology.

[94]  M. Lazdunski,et al.  Inhalational anesthetics activate two-pore-domain background K+ channels , 1999, Nature Neuroscience.

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

[96]  M. Sanguinetti,et al.  Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits* , 1999, The Journal of Biological Chemistry.

[97]  A. Wilde,et al.  A Dominant Negative Isoform of the Long QT Syndrome 1 Gene Product* , 1998, The Journal of Biological Chemistry.

[98]  S. Grissmer Potassium channels still hot. , 1997, Trends in pharmacological sciences.

[99]  R. MacKinnon,et al.  A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels. , 1992, Science.

[100]  Mark Leppert,et al.  A novel potassium channel gene, KCNQ2, is mutated in an inherited epilepsy of newborns , 1998, Nature Genetics.

[101]  B. Wollnik,et al.  Pathophysiological Mechanisms of Dominant and Recessive Kvlqt1 K + Channel Mutations Found in Inherited Cardiac Arrhythmias , 1997 .

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

[103]  O. Pongs Structural basis of voltage-gated K+ channel pharmacology. , 1992, TIPS - Trends in Pharmacological Sciences.

[104]  Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome. , 1999, Circulation research.

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

[106]  M. Blanar,et al.  KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[107]  R. Kass,et al.  MinK-KvLQT1 Fusion Proteins, Evidence for Multiple Stoichiometries of the Assembled I sK Channel* , 1998, The Journal of Biological Chemistry.

[108]  H. Higashida,et al.  Both linopirdine- and WAY123,398-sensitive components of IK(M,ng) are modulated by cyclic ADP ribose in NG108–15 cells , 2000, Pflügers Archiv.

[109]  M. Keating,et al.  Molecular basis of the long-QT syndrome associated with deafness. , 1997, The New England journal of medicine.

[110]  N. Akaike,et al.  Inhibition of M-type K+ current by linopirdine, a neurotransmitter-release enhancer, in NG108-15 neuronal cells and rat cerebral neurons in culture , 1998, Brain Research.

[111]  L. Salkoff,et al.  Calcium sensitivity of BK-type KCa channels determined by a separable domain , 1994, Neuron.

[112]  J P Roche,et al.  Reconstitution of Muscarinic Modulation of the KCNQ2/KCNQ3 K+ Channels That Underlie the Neuronal M Current , 2000, The Journal of Neuroscience.

[113]  Michael A Rogawski,et al.  KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy , 2000, Trends in Neurosciences.

[114]  Edmund M Talley,et al.  TASK-1, a Two–Pore Domain K+ Channel, Is Modulated by Multiple Neurotransmitters in Motoneurons , 2000, Neuron.

[115]  Y. Kurachi,et al.  Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers. , 2000, Pharmacology & therapeutics.

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

[117]  D. Papazian Potassium Channels Some Assembly Required , 1999, Neuron.

[118]  S. Goldstein,et al.  ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[119]  C. Kung,et al.  YKC1 encodes the depolarization‐activated K+ channel in the plasma membrane of yeast , 1995, FEBS letters.

[120]  S. Goldstein,et al.  MinK Residues Line a Potassium Channel Pore , 1996, Neuron.

[121]  L Goldman,et al.  The autopsy in clinical medicine. , 1989, Mayo Clinic proceedings.

[122]  M. Curtis,et al.  Which cardiac potassium channel subtype is the preferable target for suppression of ventricular arrhythmias? , 1996, Pharmacology & therapeutics.

[123]  F. Lang,et al.  Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes. , 1994, Molecular pharmacology.

[124]  J. Haley,et al.  Bradykinin, But Not Muscarinic, Inhibition of M-Current in Rat Sympathetic Ganglion Neurons Involves Phospholipase C-β4 , 2000, The Journal of Neuroscience.

[125]  V. Nickolson,et al.  DuP 996 (3,3‐bis(4‐pyrindinylmethyl)‐1‐phenylindolin‐2‐one) enhances the stimulus‐induced release of acetylcholine from rat brain in vitro and in vivo , 1990 .

[126]  M. Lazdunski,et al.  TRAAK Is a Mammalian Neuronal Mechano-gated K+Channel* , 1999, The Journal of Biological Chemistry.

[127]  R. North,et al.  Calcium-activated potassium channels expressed from cloned complementary DNAs , 1992, Neuron.

[128]  S. Boehm,et al.  Modulation of Spontaneous and Stimulation‐Evoked Transmitter Release from Rat Sympathetic Neurons by the Cognition Enhancer Linopirdine: Insights into Its Mechanisms of Action , 1999, Journal of neurochemistry.

[129]  F. Lehmann-Horn,et al.  Voltage-gated ion channels and hereditary disease. , 1999, Physiological reviews.