Trends in ion channel drug discovery: advances in screening technologies.

Abstract Ion channels mediate and regulate crucial electrical functions throughout the body. They are therapeutic drug targets for a variety of disorders and, in some cases, the direct cause of unwanted side-effects. Advances in medical genetics have increased our knowledge of ion channel structure–function relationships and identified disease-causing mutations in ion channel genes. The recognized importance of these proteins in health and disease has led to an active search for ion channel targets in the multi-billion-dollar worldwide drug discovery market. Trends in ion channel screening technologies have focused on increasing throughput and enhancing information content of assays through electrophysiological approaches. The ability to study ion channels by voltage clamp and their time-, voltage- and state-dependent drug interactions with enhanced throughput will ultimately play a key role in the development of novel, safe ion channel-targeted drugs.

[1]  P. Negulescu,et al.  High-throughput screening strategies for cardiac ion channels. , 2001, Trends in cardiovascular medicine.

[2]  G. Breithardt,et al.  KCNE1 mutations cause Jervell and Lange-Nielsen syndrome , 1997, Nature Genetics.

[3]  J. Tate,et al.  Potassium channels: structures, models, simulations. , 2002, Biochimica et biophysica acta.

[4]  E. Hoffman,et al.  Voltage-gated ion channelopathies: inherited disorders caused by abnormal sodium, chloride, and calcium regulation in skeletal muscle. , 1995, Annual review of medicine.

[5]  W. Haverkamp,et al.  Molecular genetics of arrhythmias – a new paradigm , 2000, Zeitschrift für Kardiologie.

[6]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.

[7]  Reshma R. Desai,et al.  Extracellular Sodium Interacts with the HERG Channel at an Outer Pore Site , 2002, The Journal of general physiology.

[8]  A. George,et al.  Molecular mechanism for an inherited cardiac arrhythmia , 1995, Nature.

[9]  D M Roden,et al.  The long QT syndromes: genetic basis and clinical implications. , 2000, Journal of the American College of Cardiology.

[10]  Hao Wang,et al.  Functional and pharmacological properties of canine ERG potassium channels. , 2003, American journal of physiology. Heart and circulatory physiology.

[11]  Samuel F. Berkovic,et al.  Genetics of the Epilepsies , 2001, Epilepsia.

[12]  W. Catterall.  Structure and function of voltage-gated ion channels. , 1995, Annual review of biochemistry.

[13]  C. January,et al.  [3H]dofetilide binding to HERG transfected membranes: a potential high throughput preclinical screen. , 2001, European journal of pharmacology.

[14]  L. Ptáček,et al.  Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system , 1997, Neuromuscular Disorders.

[15]  Neil E. Bowles,et al.  The “Final Common Pathway” Hypothesis and Inherited Cardiovascular Disease The Role of Cytoskeletal Proteins in Dilated Cardiomyopathy , 2000, Herz.

[16]  R. Griggs,et al.  Andersen's syndrome: A distinct periodic paralysis , 1997, Annals of neurology.

[17]  Rita R. Patel,et al.  A High-Throughput HERG Potassium Channel Function Assay: An Old Assay with a New Look , 2002, Drug development and industrial pharmacy.

[18]  Lori L. Isom,et al.  Auxiliary subunits of voltage-gated ion channels , 1994, Neuron.

[19]  G. Celesia,et al.  Disorders of membrane channels or channelopathies , 2001, Clinical Neurophysiology.

[20]  S. Priori,et al.  Evidence for a Cardiac Ion Channel Mutation Underlying Drug‐Induced QT Prolongation and Life‐Threatening Arrhythmias , 2000, Journal of cardiovascular electrophysiology.

[21]  A. Ebneth.  Ion channel screening technologies: will they revolutionize drug discovery? , 2002, Drug discovery today.

[22]  M. Sanguinetti,et al.  Mutations in the hminK gene cause long QT syndrome and suppress lKs function , 1997, Nature Genetics.

[23]  Arthur J Moss,et al.  SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome , 1995, Cell.

[24]  W. Catterall,et al.  From Ionic Currents to Molecular Mechanisms The Structure and Function of Voltage-Gated Sodium Channels , 2000, Neuron.

[25]  Rigler,et al.  Functional immobilisation of the nicotinic acetylcholine receptor in tethered lipid membranes , 2000, Biophysical chemistry.

[26]  P. Bennett,et al.  Human Ether-à-go-go–related Gene K+ Channel Gating Probed with Extracellular Ca2+ , 1999, The Journal of general physiology.

[27]  B Attali,et al.  Localization of a potassium channel gene (KCNE1) to 21q22.1-q22.2 by in situ hybridization and somatic cell hybridization. , 1993, Genomics.

[28]  S S Chatterjee,et al.  Congenital Q-T prolongation syndrome. , 1986, Indian heart journal.

[29]  P Coumel,et al.  Exclusion of KCNE1 (IsK) as a candidate gene for Jervell and Lange-Nielsen syndrome. , 1996, Journal of molecular and cellular cardiology.

[30]  M. Sanguinetti,et al.  Long QT Syndrome: , 2000, Journal of cardiovascular electrophysiology.

[31]  T. Jentsch,et al.  Ion channel diseases. , 2002, Human molecular genetics.

[32]  P. Bennett,et al.  Modulation of HERG potassium channels by extracellular magnesium and quinidine. , 1999, Journal of cardiovascular pharmacology.

[33]  Yan Zhang,et al.  Identification of endogenous outward currents in the human embryonic kidney (HEK 293) cell line , 1998, Journal of Neuroscience Methods.

[34]  Carlo Napolitano,et al.  Erratum: Long QT syndrome patients with mutations on the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate: Implications for gene-specific therapy (Circulation (1995) 92 (3381-3386)) , 1996 .

[35]  G. Terstappen,et al.  Functional analysis of native and recombinant ion channels using a high-capacity nonradioactive rubidium efflux assay. , 1999, Analytical biochemistry.

[36]  Jeffrey R. Balser,et al.  A Novel Extracellular Calcium Sensing Mechanism in Voltage-Gated Potassium Ion Channels , 2001, The Journal of Neuroscience.

[37]  S. Priori,et al.  Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. , 1995, Circulation.

[38]  John C. Rogers,et al.  Functional Roles of the Extracellular Segments of the Sodium Channel α Subunit in Voltage-dependent Gating and Modulation by β1 Subunits* , 1999, The Journal of Biological Chemistry.

[39]  V. Gribkoff,et al.  An assessment of the present and future roles of non-ligand gated ion channel modulators as CNS therapeutics. , 1999, Expert opinion on pharmacotherapy.

[40]  B. Hille,et al.  Ionic channels of excitable membranes , 2001 .

[41]  Lei Wu,et al.  Ion-channel assay technologies: quo vadis? , 2001, Drug discovery today.

[42]  Michael Fejtl,et al.  The roboocyte: automated cDNA/mRNA injection and subsequent TEVC recording on Xenopus oocytes in 96-well microtiter plates. , 2003, Receptors & channels.

[43]  Patrice Roll,et al.  Epilepsy and ionic channels. , 2002, Epileptic disorders : international epilepsy journal with videotape.

[44]  A J Moss,et al.  Spectrum of Mutations in Long-QT Syndrome Genes: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 , 2000, Circulation.

[45]  Jeffrey R. Balser,et al.  A sensitive mechanism for cation modulation of potassium current , 2000, Nature Neuroscience.

[46]  B. Sakmann,et al.  Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches , 1981, Pflügers Archiv.

[47]  Derek J Trezise,et al.  IonWorks™ HT: A New High-Throughput Electrophysiology Measurement Platform , 2003, Journal of biomolecular screening.

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

[49]  R L Barchi,et al.  Ion channel mutations affecting muscle and brain. , 1998, Current opinion in neurology.

[50]  Youxing Jiang,et al.  The open pore conformation of potassium channels , 2002, Nature.

[51]  W. Catterall.  Structure and regulation of voltage-gated Ca2+ channels. , 2000, Annual review of cell and developmental biology.

[52]  W. Haverkamp,et al.  The LQT syndromes – current status of molecular mechanisms , 1999, Zeitschrift für Kardiologie.

[53]  G. Robertson,et al.  HERG, a human inward rectifier in the voltage-gated potassium channel family. , 1995, Science.

[54]  J. Balser,et al.  Probing the Interaction Between Inactivation Gating and d-Sotalol Block of HERG , 2000, Circulation research.

[55]  Aj Butcher,et al.  Evidence for Two Concentration-Dependent Processes for β-Subunit Effects on α1B Calcium Channels , 2001 .

[56]  M J Ackerman,et al.  The long QT syndrome: ion channel diseases of the heart. , 1998, Mayo Clinic proceedings.

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

[58]  Paul B Bennett,et al.  High throughput ion-channel pharmacology: planar-array-based voltage clamp. , 2003, Assay and drug development technologies.

[59]  N. Dascal,et al.  The use of Xenopus oocytes for the study of ion channels. , 1987, CRC critical reviews in biochemistry.

[60]  David Owen,et al.  CHANNELLING DISCOVERY current trends in ion channel drug discovery research , 2002 .

[61]  H. Lester,et al.  Time Resolved Kinetics of Direct Gβ1γ2 Interactions with the Carboxyl Terminus of Kir3.4 Inward Rectifier K+ Channel Subunits , 1996, Neuropharmacology.

[62]  M. Keating,et al.  The long QT syndrome. A review of recent molecular genetic and physiologic discoveries. , 1996, Medicine.

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

[64]  Brian Cox,et al.  HTS approaches to voltage-gated ion channel drug discovery , 1998 .