Pediatric Cardiology

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Pediatric Cardiology

  1. 1. Ion Channels in the Cardiovascular System in Health and Disease William A. Coetzee [email_address] Tel: 263-8518
  2. 2. Hearts are Composed of Cells
  3. 3. The Cardiac Myocyte
  4. 4. Cells Have Membranes
  5. 6. Channels Pore Filter Gate
  6. 7. Patch Clamping
  7. 9. closed open
  8. 11. Ion Channels - Gating <ul><li>A seminal contribution of Hodgkin and Huxley (circa 1940): channels transit among various conformational states </li></ul><ul><li>Activation: process of channel opening during depolarization </li></ul><ul><li>Inactivation: channels shut during maintained depolarization </li></ul>
  9. 12. Inward Currents Outward Currents K + Na + Ca 2+ Na + K + Ca 2+ Cl - Cl - Cl - + +
  10. 13. Ion Channels <ul><li>Na + channels </li></ul><ul><li>Ca 2+ channels </li></ul><ul><li>K + channels </li></ul><ul><li>Exchangers </li></ul><ul><li>Pumps </li></ul>
  11. 14. Na + Channels - Electrophysiology <ul><li>Rapidly activating and inactivating </li></ul><ul><li>A heart cell typically expresses more than 100,000 Na + channels </li></ul><ul><li>Responsible for the rapid upstroke of the cardiac action potential, and for rapid impulse conduction through cardiac tissue </li></ul>
  12. 15. Ion Channels – The Traditional View of the Biophysicist Ions move through “holes” in the membrane as a result of the electro-chemical driving force (flow of electrical current) The “holes” are selective in that only certain ions are allowed to pass (i.e. Na + or K + or Ca 2+ , etc) The “holes” or “channels” open and close randomly, but open kinetics are influenced by a) voltage and b) time in out +
  13. 16. Ion Channels are Transmembrane Proteins <ul><li>The first molecular components of channels were identified only about a decade ago by molecular cloning methods </li></ul><ul><li>The availability of channel cDNAs has allowed enormous progress in the understanding of the structure and molecular mechanisms of function of ion channels </li></ul><ul><li>In addition to the pore forming or principal subunits (often called  subunits), which determine the infrastructure of the channel, many channels (K + , Na + and Ca 2+ channels), contain auxiliary proteins that can modify the properties of the channels </li></ul>
  14. 17. Recent Advances <ul><li>Important new insights into the mechanisms of ionic selectivity, voltage- and calcium-dependent gating, inactivation and blockade of these channels have been obtained </li></ul><ul><li>These efforts recently culminated with the crystallization and high resolution structural analysis of a K + channel </li></ul>
  15. 18. The Na + Channel  -Subunit Four repeating units. Each domain folds into six transmembrane helices
  16. 19. Na + Channels - Structure <ul><li>Consist of various subunits, but only the principal (  ) subunit is required for function </li></ul><ul><li>Four internally homologous domains (labeled I-IV) </li></ul><ul><li>The four domains fold together so as to create a central pore </li></ul>Marban et al, J Physiol (1998), 508.3, pp. 647-657
  17. 20. Na + Channels: Structural elements of activation <ul><li>S4 segments serve as the activation sensors </li></ul><ul><li>Charged residues in each S4 segment physically traverse the membrane </li></ul><ul><li>Where are the activation gates? </li></ul>
  18. 21. Structural Elements of Gating and Selectivity
  19. 22. <ul><li>Multiple inactivation processes exist </li></ul><ul><li>Fast inactivation is mediated partly by the cytoplasmic linker between domains III and IV </li></ul><ul><li>Slow inactivation? </li></ul>Na + Channels: Structural elements of inactivation
  20. 24. Principal and Auxiliary Subunits of Ion Channels
  21. 25. Na + -Channels Modulation by auxiliary subunits <ul><li>Two distinct subunits (  1 and  2) </li></ul><ul><li>Both contain: </li></ul><ul><ul><li>a small carboxy-terminal cytoplasmic domain, </li></ul></ul><ul><ul><li>a single membrane-spanning segment, and </li></ul></ul><ul><ul><li>a large amino-terminal extracellular domain with several consensus sites for N-linked glycosylation and immunoglobulin-like folds </li></ul></ul><ul><li>The  1 subunit is widely expressed in skeletal muscle, heart and neuronal tissue, and is encoded by a single gene (SCN1B) </li></ul>
  22. 26. Na + -Channels : Genetic Disorders <ul><li>Congenital long-QT syndrome (LQT3) </li></ul><ul><ul><li>Mutations in the cardiac Na-channel gene (SCN5A) </li></ul></ul><ul><ul><li>Slowed inactivation </li></ul></ul><ul><ul><li>Mutations reside at loci consistent with this gating effect </li></ul></ul>Persistent inward current during AP repolarization, prolonging the QT interval and setting the stage for fatal ventricular arrhythmias
  23. 27. <ul><li>Local anaesthetics (class I antiarrhythmic agents) block Na+ channels in a voltage-dependent manner (S6 segment of domain IV) </li></ul><ul><li>Block is enhanced at depolarized potentials and/or with repetitive pulsing - modulated receptor model </li></ul><ul><li>Neurotoxins : tetrodotoxin (TTX) interacts with a particular residue in the P region of domain I </li></ul><ul><li>µ-conotoxins </li></ul><ul><li>Sea anemone (e.g. anthopleurin A and B, ATX II) and scorpion toxins inhibit Na + channel inactivation by binding to sites that include the S3-S4 extracellular loop of domain IV </li></ul>Na + Channels - Pharmacology
  24. 28. Ion Channels <ul><li>Na + channels </li></ul><ul><li>Ca 2+ channels </li></ul><ul><li>K + channels </li></ul><ul><li>Exchangers </li></ul><ul><li>Pumps </li></ul>
  25. 29. Ca 2+ Channels: Electrophysiology <ul><li>Calcium influx through voltage-dependent calcium channels triggers excitation-contraction coupling and regulates pacemaking activity in the heart. </li></ul><ul><li>Multiple Ca 2+ currents: </li></ul><ul><ul><li>L, N, P, Q, R and T-type </li></ul></ul>
  26. 30. Two types of Ca 2+ Currents in Heart <ul><li>L-type Ca 2+ Current </li></ul><ul><ul><li>High-voltage-activated </li></ul></ul><ul><ul><li>Slow inactivation (>500ms) </li></ul></ul><ul><ul><li>Large conductance (25pS) </li></ul></ul><ul><ul><li>DHP-sensitive </li></ul></ul><ul><ul><li>Requirement of phosphorylation </li></ul></ul><ul><ul><li>Essential in triggering Ca 2+ release from internal stores </li></ul></ul><ul><li>T-type Ca 2+ Current </li></ul><ul><ul><li>Low-voltage-activated </li></ul></ul><ul><ul><li>Low threshold of activation </li></ul></ul><ul><ul><li>Small conductance (8pS) </li></ul></ul><ul><ul><li>Slow activation & fast inactivation </li></ul></ul><ul><ul><li>Slow deactivation!! </li></ul></ul><ul><ul><li>Blocked by mibefradil and Ni 2+ ions </li></ul></ul><ul><ul><li>Role in pacemaker activity? </li></ul></ul>
  27. 31. The  -subunit is known to contain the ion channel filter and has gating properties The β-subunit is situated intracellularly and is involved in the membrane trafficking of α1-subunits. The γ-subunit is a glycoprotein having four transmembrane segments. The  2-subunit is a highly glycosylated extracellular protein that is attached to the membrane-spanning δ-subunit by means of disulfide bonds. The α2-subunit provides structural support whilst the δ-subunit modulates the voltage-dependent activation and steady-state inactivation of the channel
  28. 32. Ca 2+ Channel  -Subunits Molecular Composition 17q23  CACLNB1 17q11.2-22  1 CACLNB1 7q21-22  2  CACLN1L21 Brain, heart 17q22 T-type  1G CACLNA1G Brain, heart 1q25-31 R-type?  1E CACLN1A6 Endocrine, brain 3p14.3 L-type  1D CACLN1A2 Heart, VSM 12p13.3 L-type  1C CACLN1A1 Neuronal 9q34 N-type  1B CACLN1A5 Neuronal 19p13.1 P/Q-type  1A CACLN1A4 Skeletal 1q31-32 L-type  1S CACLN1A3 Tissue Chromosome Type Protein Gene
  29. 33. Ca 2+ Channel  -Subunits Structural elements of function
  30. 34. Ca 2+ Channel  -Subunits Genetic Disorders <ul><li>Skeletal muscle </li></ul><ul><li>Mutations in CACNL1A3 (  1S L-type skeletal muscle subunit) </li></ul><ul><ul><li>Hypokalemic periodic paralysis </li></ul></ul><ul><ul><li>Malignant hyperthermia (mostly associated with RYR2) </li></ul></ul><ul><li>Neuronal </li></ul><ul><li>Mutations in CACNL1A4 (  1A P/Q-type skeletal muscle subunit) </li></ul><ul><ul><li>Familial hemiplegic migraine </li></ul></ul><ul><ul><li>Episodic ataxia </li></ul></ul><ul><ul><li>Spinocerebellar ataxia type-6 </li></ul></ul>
  31. 35. Skeletal Ca 2+ Channel  -Subunits Genetic Disorders Hyperkalemic periodic paralysis Malignant hyperthermia
  32. 36. Ca 2+ Channels: Pharmacology <ul><li>Three main classes of Ca 2+ channel blockers: </li></ul><ul><ul><li>Phenylalkylamines (verapamil) </li></ul></ul><ul><ul><li>Benzothiazipines (diltiazem) </li></ul></ul><ul><ul><li>Dihydropyridines (nifedipine) </li></ul></ul><ul><li>Bind to separate sites of the  -subunit (common site: TMs 5&6 of repeat II and TM6 of repeat IV) – equivalent region in Na + channel causes block by local anesthetics </li></ul>
  33. 37. Ion Channels <ul><li>Na + channels </li></ul><ul><li>Ca 2+ channels </li></ul><ul><li>K + channels </li></ul><ul><li>Exchangers </li></ul><ul><li>Pumps </li></ul>
  34. 38. Functional Diversity of K + Channels in the Heart <ul><li>Voltage-activated K + Channels </li></ul><ul><li>Inward rectifiers </li></ul><ul><li>“Leak” K + currents </li></ul>
  35. 39. Voltage-activated K + Channels Responsible for repolarization of the action potential and refractoriness (consequences for contractility and arrhythmias) K + K + + Voltage-activated K + - Inward rectifier K + “ Leak”
  36. 40. Inward Rectifier K + Channels Setting the resting potential and automaticity. Also responsible for repolarization of the action potential and refractoriness (consequences for contractility and arrhythmias) K + K + + Voltage-activated K + - Inward rectifier K + “ Leak”
  37. 41. Leak K + Channels <ul><li>Plateau (I KP ) K + channels </li></ul>“ Leak” K + channels : Controlling action potential duration? K + K + + Voltage-activated K + - Inward rectifier K + “ Leak”
  38. 42. K + Channels - Structure <ul><li>Both  (principal) and  (auxiliary) subunits exist </li></ul><ul><li>Fortuitous correlation exists between the classification system based on function and that based on structure </li></ul>
  39. 43. K + Channel Principal Subunits Voltage-gated K + channels Ca 2+ -activated K+ channels “ Leak” K + channels Inward Rectifier K + channels 6 TMD 4 TMD 2 TMD Coetzee, 2001
  40. 44. K + Channel Principal and Auxiliary Subunits Voltage-gated K + channels Ca 2+ -activated K+ channels “ Leak” K + channels Inward Rectifier K + channels 6 TMD 4 TMD 2 TMD eag KCNQ SK slo Kv eag erg elk Kv1 Kv2 Kv3 Kv4 Kv5 Kv6 Kv8 Kv9 Kir1 Kir2 Kir3 Kir4 Kir5 Kir6 Kir7 KCNK1 KCNK9 KCNK2 KCNK10 KCNK3 KCNK12 KCNK4 KCNK13 KCNK5 KCNK15 KCNK6 KCNK16 KCNK7 KCNK17 Kir SUR KCR1 minK MiRPs Kv  KChAP KChIPs NCS1 Coetzee, 2001
  41. 45. Voltage-activated K + Channels <ul><li>Transient outward current (I to ) </li></ul><ul><li>Slowly activating delayed rectifier (I Ks ) </li></ul><ul><li>Rapidly activating delayed rectifier (I Kr ) </li></ul><ul><li>Ultra-rapidly activating delayed rectifier (I Kur ) </li></ul>Responsible for repolarization of the action potential and refractoriness (consequences for contractility and arrhythmias)
  42. 46. Transient Outward K + Channels <ul><li>Rapidly activating, slow inactivation </li></ul><ul><li>Responsible for early repolarization (Purkinje fibers) </li></ul><ul><li>Also contributes to late repolarization </li></ul>
  43. 47. Compounds Blocking I to <ul><li>Cations </li></ul><ul><ul><li>TEA, Cs + , 4-AP </li></ul></ul><ul><li>Class I </li></ul><ul><ul><li>Disopyramide </li></ul></ul><ul><ul><li>Quinidine </li></ul></ul><ul><ul><li>Flecainide </li></ul></ul><ul><ul><li>Propafenone </li></ul></ul><ul><li>Class III </li></ul><ul><ul><li>Tedisamil </li></ul></ul><ul><li>Other </li></ul><ul><ul><li>Caffeine, Ryanodine </li></ul></ul><ul><ul><li>Bepridil </li></ul></ul><ul><ul><li>D-600 </li></ul></ul><ul><ul><li>Nifedipine </li></ul></ul><ul><ul><li>Imipramine </li></ul></ul>
  44. 48. Delayed Rectifier Currents I Kr and I Ks
  45. 49. Delayed Rectifier Current Matsuura et al, 1987 Control Ca-free + Cd
  46. 50. Two Types of Delayed Rectifiers Sanguinetti & Jurkiewicz, 1991 E-4031 550 ms 100 pA
  47. 51. Compounds Blocking Delayed Rectifiers <ul><li>Rapidly activating (I Kr ) </li></ul><ul><ul><li>E-4031 </li></ul></ul><ul><ul><li>Dofetilide </li></ul></ul><ul><ul><li>Sematilide </li></ul></ul><ul><ul><li>MK-499 </li></ul></ul><ul><ul><li>La 3+ </li></ul></ul><ul><li>Slowly activating (I Ks ) </li></ul><ul><ul><li>K + sparing diuretics </li></ul></ul><ul><ul><ul><li>Indapamide </li></ul></ul></ul><ul><ul><ul><li>Triamterene </li></ul></ul></ul>
  48. 52. K + Channel  -Subunits Molecular determinants of gating N-type inactivation pore S4 segment
  49. 53. Kv  Subunits Accelerate Inactivation of Kv Channels
  50. 54. Kv  Subunits Increase Expression Levels of Kv Channels
  51. 55. Enhanced Surface Expression
  52. 56. Kv  Subunits as Molecular Chaperones
  53. 57. 3-Dimensional Structure of Kv  2
  54. 58. Kv  Confers Hypoxia-Sensitivity to Kv4 Channels
  55. 59. Identification of Frequenin as a Putative Kv4  -subunit <ul><li>We searched EST databases (using KChIP2 as a bait) </li></ul><ul><li>Concentrated on ESTs cloned from cardiac libraries </li></ul><ul><li>W81153 : frequenin (cloned from a human fetal cardiac library) </li></ul>
  56. 60. Effects of Frequenin on Kv4.2 Currents Kv4.2 + H 2 O Kv4.2 + Frequenin 0 5 10 15 20 * Kv4.2+Frequenin Kv4.2+H 2 O 100 ms 10  A
  57. 61. Frequenin Enhances Kv4.2 Membrane Trafficking Kv4.2 Frequenin-GFP Kv4.2 + frequenin-GFP Anti-Kv4.2 Ab Anti-Kv4.2 Ab COS-7 cells
  58. 62. Delayed Rectifier K + Channels Molecular Composition <ul><li>Rapidly-activating delayed rectifier </li></ul><ul><ul><li>NCNH2 (h-erg) </li></ul></ul><ul><li>Slowly-activating delayed rectifier </li></ul><ul><ul><li>KCNQ1 (KvLQT1) plus KCNE1 (minK) </li></ul></ul><ul><li>Ultra-rapidly activating delayed rectifier </li></ul><ul><ul><li>Kv1.5? </li></ul></ul>
  59. 63. Voltage-activated K + Channels Pharmacology <ul><li>Transient outward current </li></ul><ul><ul><li>4-AP, bupivacaine, quinidine, profafenone, sotalol, capsaicin, verapamil, nifedipine </li></ul></ul><ul><li>Rapidly-activating delayed rectifier </li></ul><ul><ul><li>E-4031, dofetilide, sotalol, amiodarone, etc. </li></ul></ul><ul><li>Slowly-activating delayed rectifier </li></ul><ul><ul><li>Quinidine, amiodarone, clofilium, indapamide </li></ul></ul><ul><li>Ultrarapid delayed rectifier </li></ul><ul><ul><li>4-AP, clofilium </li></ul></ul>
  60. 64. Voltage-activated K + Channels Genetic Disorders 11p15.5 21q22.1- 21q22.2 LQT1 (Romano-Ward) (Jervall-Lange-Nielsen) KvLQT1 minK KCNQ1 KCNE1 7q35-7q36 LQT2 H-erg NCNH2 12p13 Episodic Ataxia Kv1.1 NCNA1 Chromosome Disease Channel Gene
  61. 65. Mechanisms of Arrhythmias <ul><li>Abnormal automaticity </li></ul><ul><li>Triggered activity </li></ul><ul><li>Reentry </li></ul>
  62. 66. Triggered Activity <ul><li>Arrhythmias originating from afterdepolarizations </li></ul><ul><ul><li>Early afterdepolarizations (phases 2 or 3) </li></ul></ul><ul><ul><li>Delayed afterdepolarizations (phase 4) </li></ul></ul><ul><li>If large enough, can engage Na + /Ca 2+ channels and initiate an action potential </li></ul>
  63. 68. Early Afterdepolarizations <ul><li>Can occur when outward currents are inhibited or inward currents are enhanced </li></ul><ul><li>Generally seen under conditions that prolong the action potential: </li></ul><ul><ul><li>Hypokalemia, hypomagnesemia </li></ul></ul><ul><ul><li>Antiarrhythmic drugs </li></ul></ul><ul><li>Proposed mechanism for Torsades de Pointes </li></ul>
  64. 70. Factors Promoting EADs <ul><li>Autonomic - increased sympathetic tone - increased catecholamines - decreased parasympathetic </li></ul><ul><li>Metabolic - hypoxia - acidosis </li></ul><ul><li>Electrolytes - Cesium - Hypokalemia </li></ul>
  65. 71. Factors Promoting EADs <ul><li>Drugs - Sotalol - N-acetylprocainamide - Quinidine </li></ul><ul><li>Heart rate - Bradycardia </li></ul>
  66. 72. Inward Rectifier K + Channels <ul><li>The “classical” inward rectifier (I K1 ) </li></ul><ul><li>G protein-activated K + channels (I K,Ach ; I K,Ado ) </li></ul><ul><li>ATP-sensitive K+ channels (I K,ATP ) </li></ul><ul><li>Na + -activated K + channels </li></ul>Inward rectifier K + channels : Setting the resting potential and automaticity. Also responsible for repolarization of the action potential and refractoriness (consequences for contractility and arrhythmias) K + K + + Voltage-activated K + - Inward rectifier K + “ Leak”
  67. 73. Inward Rectifier K + Channels Electrophysiology <ul><li>Outward current under physiological conditions </li></ul><ul><li>Less outward current when membrane is depolarized </li></ul><ul><li>Open at all voltages </li></ul>Set the resting potential and automaticity. Also responsible for repolarization of the action potential and refractoriness (consequences for contractility and arrhythmias)
  68. 74. Inward Rectifier K + Channels Structure <ul><li>Two transmembrane domains </li></ul><ul><li>Pore </li></ul><ul><li>No voltage sensor </li></ul>
  69. 75. K + Channel Principal Subunits Voltage-gated K + channels Ca 2+ -activated K+ channels “ Leak” K + channels Inward Rectifier K + channels 6 TMD 4 TMD 2 TMD Coetzee, 2001
  70. 76. K + Channel Principal and Auxiliary Subunits Voltage-gated K + channels Ca 2+ -activated K+ channels “ Leak” K + channels Inward Rectifier K + channels 6 TMD 4 TMD 2 TMD eag KCNQ SK slo Kv eag erg elk Kv1 Kv2 Kv3 Kv4 Kv5 Kv6 Kv8 Kv9 Kir1 Kir2 Kir3 Kir4 Kir5 Kir6 Kir7 KCNK1 KCNK9 KCNK2 KCNK10 KCNK3 KCNK12 KCNK4 KCNK13 KCNK5 KCNK15 KCNK6 KCNK16 KCNK7 KCNK17 Kir SUR KCR1 minK MiRPs Kv  KChAP KChIPs NCS1 Coetzee, 2001
  71. 77. Inward Rectifier K + Channels Genetic Disorders 12p11.23 12p12.1 Vasospastic angina?? (Printzmetal’s angina) Kir6.1 SUR2 KCNJ8 ABCC9 11p15.1 Familial persistent hyperinsulinemic hypoglycemia of infancy Kir6.2 (ATP-sensitive K + channel; pancreas) KCNJ11 17q23.1-q24.2 Anderson’s sydrome Kir2.1 KCNJ2 11p15.1 Familial persistent hyperinsulinemic hypoglycemia of infancy SUR1 ABCC8 11q24 Bartter’s syndrome Kir1.1 (ATP-activated K + channel; renal) KCNJ1 Chromosome Disease Channel Gene
  72. 78. Inward Rectifier K + Channels Pharmacology <ul><li>“Classical” inward rectifiers </li></ul><ul><ul><li>Ba 2+ , Cs + </li></ul></ul><ul><li>G protein-activated K + channels </li></ul><ul><ul><li>Acetylcholine, adenosine (mainly in atria) </li></ul></ul><ul><li>ATP-sensitive K + channels </li></ul><ul><ul><li>Blocked by glibenclamide </li></ul></ul><ul><ul><li>Opened by pinacidil, cromakalim, nicorandil </li></ul></ul>
  73. 79. K + Channel Principal and Auxiliary Subunits Voltage-gated K + channels Ca 2+ -activated K+ channels “ Leak” K + channels Inward Rectifier K + channels 6 TMD 4 TMD 2 TMD eag KCNQ SK slo Kv eag erg elk Kv1 Kv2 Kv3 Kv4 Kv5 Kv6 Kv8 Kv9 Kir1 Kir2 Kir3 Kir4 Kir5 Kir6 Kir7 KCNK1 KCNK9 KCNK2 KCNK10 KCNK3 KCNK12 KCNK4 KCNK13 KCNK5 KCNK15 KCNK6 KCNK16 KCNK7 KCNK17 Kir SUR KCR1 minK MiRPs Kv  KChAP KChIPs NCS1 Coetzee, 2001
  74. 80. Role of the K ATP Channel <ul><ul><ul><ul><ul><li>Inagaki et al, 1995 </li></ul></ul></ul></ul></ul>
  75. 81. Secretory Mechanisms <ul><li>Apocrine secretion occurs when the release of secretory materials is accompanied with loss of part of cytoplasm </li></ul><ul><li>Holocrine secretion ; the entire cell is secreted into the glandular lumen </li></ul><ul><li>Exocytosis is the most commonly occurring type of secretion; here the secretory materials are contained in the secretory vesicles and released without loss of cytoplasm </li></ul>
  76. 82. Mechanism of Insulin Release <ul><li>Fasting state </li></ul><ul><ul><li>Low cytosolic glucose </li></ul></ul><ul><ul><li>KATP channels are unblocked </li></ul></ul><ul><ul><li>High K+ conductance </li></ul></ul><ul><ul><li>Negative resting potential </li></ul></ul> - cell K +
  77. 83. <ul><li>After a meal </li></ul><ul><ul><li>Glucose taken up </li></ul></ul><ul><ul><li>Glycolysis </li></ul></ul><ul><ul><li>K ATP channels blocked </li></ul></ul><ul><ul><li>Depolarization </li></ul></ul><ul><ul><li>Ca 2+ influx </li></ul></ul><ul><ul><li>Secretory insulin release stimulated </li></ul></ul>Mechanism of Insulin Release ATP Glucose Ca 2+ Insulin Depolarization
  78. 84. Inward Rectifier K + Channels Genetic Disorders 12p11.23 12p12.1 Vasospastic angina?? (Printzmetal’s angina) Kir6.1 SUR2 KCNJ8 ABCC9 11p15.1 Familial persistent hyperinsulinemic hypoglycemia of infancy Kir6.2 (ATP-sensitive K + channel; pancreas) KCNJ11 17q23.1-q24.2 Anderson’s sydrome Kir2.1 KCNJ2 11p15.1 Familial persistent hyperinsulinemic hypoglycemia of infancy SUR1 ABCC8 11q24 Bartter’s syndrome Kir1.1 (ATP-activated K + channel; renal) KCNJ1 Chromosome Disease Channel Gene
  79. 86. Glibenclamide Blocks K ATP Channels
  80. 87. Further Reading <ul><li>Frances M. Ashcroft. Ion Channels and Disease . Academic Press, 2000 </li></ul><ul><li>Coetzee WA, Amarillo Y, Chiu J, Chow A, Lau D, McCormack T, Moreno H, Nadal MS, Ozaita A, Pountney D, Saganich M, Vega-Saenz de Miera E, Rudy B. Molecular diversity of K + channels . Ann N Y Acad Sci 1999 Apr 30;868:233-85 </li></ul>
  81. 88. Next Thursday

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