Potassium Channels Regulating the Electrical Activity of the Heart



Potassium channels govern repolarization of the action potential in the heart. Over the last 15 years, defects in their function have been revealed in a variety of hereditary and acquired diseases of heart rhythm. The most important of these is the long QT syndrome but a short QT syndrome and hereditary atrial fibrillation have also been described. In this chapter, we discuss the nature of these genetic defects and how in principle they lead to disease at the cellular level. In particular, we emphasize the role of aberrant trafficking. We also discuss the relationship to drug-induced long QT syndrome and the potential for mutation-specific therapy in the hereditary diseases.


Cystic Fibrosis Transmembrane Conductance Regulator HERG Channel Endoplasmic Reticulum Retention Trafficking Defect HERG Protein 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Noble D. The surprising heart: a review of recent progress in cardiac electrophysiology. J Physiol (Lond). 1984;353:1–50.Google Scholar
  2. 2.
    Luo CH, Rudy Y. A model of the ventricular cardiac action potential. Depolarization, repolarization, and their interaction. Circ Res. 1991;68(6):1501–26.PubMedGoogle Scholar
  3. 3.
    Boyett MR, Honjo H, Kodama I. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res. 2000;47:658–87.PubMedGoogle Scholar
  4. 4.
    Josephson IR, Sanchez-Chapula J, Brown AM. Early outward current in rat single ventricular cells. Circ Res. 1984;54(2):157–62.PubMedGoogle Scholar
  5. 5.
    Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol. 1990;96(1):195–215.PubMedGoogle Scholar
  6. 6.
    Shah AK, Cohen IS, Datyner NB. Background K+ current in isolated canine cardiac Purkinje myocytes. Biophys J. 1987;52(4):519–25.PubMedGoogle Scholar
  7. 7.
    Tinker A. The assembly and targeting of potassium channels. In: Henley J, Moss SJ, editors. The assembly and targeting of ion channels. Oxford: Oxford University Press; 2002. p. 28–57.Google Scholar
  8. 8.
    Smith PL, Baukrowitz T, Yellen G. The inward rectification mechanism of the HERG cardiac potassium channel. Nature. 1996;379(6568):833–6.PubMedGoogle Scholar
  9. 9.
    Nichols CG, Lopatin AN. Inward rectifier potassium channels. Annu Rev Physiol. 1997;59:171–91.PubMedGoogle Scholar
  10. 10.
    Warmke JW, Ganetzky B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc Natl Acad Sci U S A. 1994;91(8):3438–42.PubMedGoogle Scholar
  11. 11.
    Curran ME, Splawski I, Timothy KW, Vincent GM, Green ED, Keating MT. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell. 1995;80(5):795–803.PubMedGoogle Scholar
  12. 12.
    Sanguinetti MC, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell. 1995;81(2):299–307.PubMedGoogle Scholar
  13. 13.
    Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269(5220):92–5.PubMedGoogle Scholar
  14. 14.
    Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97(2):175–87.PubMedGoogle Scholar
  15. 15.
    Weerapura M, Nattel S, Chartier D, Caballero R, Hebert TE. A comparison of currents carried by HERG, with and without coexpression of MiRP1, and the native rapid delayed rectifier current. Is MiRP1 the missing link? J Physiol. 2002;540(Pt 1):15–27.PubMedGoogle Scholar
  16. 16.
    Decher N, Bundis F, Vajna R, Steinmeyer K. KCNE2 modulates current amplitudes and activation kinetics of HCN4: influence of KCNE family members on HCN4 currents. Pflugers Arch. 2003;446(6):633–40.PubMedGoogle Scholar
  17. 17.
    Roepke TK, Kontogeorgis A, Ovanez C, et al. Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K, slow1) and I(to, f). FASEB J. 2008;22(10):3648–60.PubMedGoogle Scholar
  18. 18.
    Brandt MC, Endres-Becker J, Zagidullin N, et al. Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties. Am J Physiol Heart Circ Physiol. 2009;297(1):H355–63.PubMedGoogle Scholar
  19. 19.
    Jiang M, Xu X, Wang Y, et al. Dynamic partnership between KCNQ1 and KCNE1 and influence on cardiac IKs current amplitude by KCNE2. J Biol Chem. 2009;284(24):16452–62.PubMedGoogle Scholar
  20. 20.
    Barhanin J, Lesage F, Guillemare E, Fink M, Lazdunski M, Romey G. K(V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature. 1996;384(6604):78–80.PubMedGoogle Scholar
  21. 21.
    Sanguinetti MC, Curran ME, Zou A, et al. Coassembly of K(V)LQT1 and minK (IsK) proteins to form cardiac I(Ks) potassium channel. Nature. 1996;384(6604):80–3.PubMedGoogle Scholar
  22. 22.
    Chen H, Kim LA, Rajan S, Xu S, Goldstein SA. Charybdotoxin binding in the I(Ks) pore demonstrates two MinK subunits in each channel complex. Neuron. 2003;40(1):15–23.PubMedGoogle Scholar
  23. 23.
    Marx SO, Kurokawa J, Reiken S, et al. Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science. 2002;295(5554):496–9.PubMedGoogle Scholar
  24. 24.
    Chen L, Kurokawa J, Kass RS. Phosphorylation of the A-kinase-anchoring protein Yotiao contributes to protein kinase A regulation of a heart potassium channel. J Biol Chem. 2005;280(36):31347–52.PubMedGoogle Scholar
  25. 25.
    Kubo Y, Baldwin TJ, Jan YN, Jan LY. Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature. 1993;362(6416):127–33.PubMedGoogle Scholar
  26. 26.
    Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev. 2010;90(1):291–366.PubMedGoogle Scholar
  27. 27.
    Ryan DP, da Silva MR, Soong TW, et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010;140(1):88–98.PubMedGoogle Scholar
  28. 28.
    Zaritsky JJ, Redell JB, Tempel BL, Schwarz TL. The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol. 2001;533(Pt 3):697–710.PubMedGoogle Scholar
  29. 29.
    Sansone V, Griggs RC, Meola G, et al. Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol. 1997;42(3):305–12.PubMedGoogle Scholar
  30. 30.
    Plaster NM, Tawil R, Tristani-Firouzi M, et al. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell. 2001;105(4):511–9.PubMedGoogle Scholar
  31. 31.
    Tristani-Firouzi M, Jensen JL, Donaldson MR, et al. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest. 2002;110(3):381–8.PubMedGoogle Scholar
  32. 32.
    Liu GX, Derst C, Schlichthorl G, et al. Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes. J Physiol. 2001;532(Pt 1):115–26.PubMedGoogle Scholar
  33. 33.
    Schram G, Melnyk P, Pourrier M, Wang Z, Nattel S. Kir2.4 and Kir2.1 K(+) channel subunits co-assemble: a potential new contributor to inward rectifier current heterogeneity. J Physiol. 2002;544(Pt 2):337–49.PubMedGoogle Scholar
  34. 34.
    Akar FG, Yan GX, Antzelevitch C, Rosenbaum DS. Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long-QT syndrome. Circulation. 2002;105(10):1247–53.PubMedGoogle Scholar
  35. 35.
    Hondeghem LM, Carlsson L, Duker G. Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation. 2001;103(15):2004–13.PubMedGoogle Scholar
  36. 36.
    Hondeghem LM. Use and abuse of QT and TRIaD in cardiac safety research: importance of study design and conduct. Eur J Pharmacol. 2008;584(1):1–9.PubMedGoogle Scholar
  37. 37.
    Myles RC, Burton FL, Cobbe SM, Smith GL. The link between repolarisation alternans and ventricular arrhythmia: does the cellular phenomenon extend to the clinical problem? J Mol Cell Cardiol. 2008;45(1):1–10.PubMedGoogle Scholar
  38. 38.
    Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–6.PubMedGoogle Scholar
  39. 39.
    Jervell A, Lange-Nielsen F. Congenital deaf-mutism, functional heart disease with prologation of Q-T interval and sudden death. Am Heart J. 1957;54:59–68.PubMedGoogle Scholar
  40. 40.
    Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102(10):1178–85.PubMedGoogle Scholar
  41. 41.
    Schulze-Bahr E, Wang Q, Wedekind H, et al. KCNE1 mutations cause jervell and Lange-Nielsen syndrome. Nat Genet. 1997;17(3):267–8.PubMedGoogle Scholar
  42. 42.
    Tyson J, Tranebjaerg L, Bellman S, et al. IsK and KvLQT1: mutation in either of the two subunits of the slow component of the delayed rectifier potassium channel can cause Jervell and Lange-Nielsen syndrome. Hum Mol Genet. 1997;6(12):2179–85.PubMedGoogle Scholar
  43. 43.
    Chen L, Marquardt ML, Tester DJ, Sampson KJ, Ackerman MJ, Kass RS. Mutation of an A-kinase-anchoring protein causes long-QT syndrome. Proc Natl Acad Sci U S A. 2007;104(52):20990–5.PubMedGoogle Scholar
  44. 44.
    Shah RR. The significance of QT interval in drug development. Br J Clin Pharmacol. 2002;54(2):188–202.PubMedGoogle Scholar
  45. 45.
    Fermini B, Fossa AA. The impact of drug-induced QT interval prolongation on drug discovery and development. Nat Rev Drug Discov. 2003;2(6):439–47.PubMedGoogle Scholar
  46. 46.
    Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation. 2003;108(8):965–70.PubMedGoogle Scholar
  47. 47.
    Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109(1):30–5.PubMedGoogle Scholar
  48. 48.
    Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109(20):2394–7.PubMedGoogle Scholar
  49. 49.
    Priori SG, Pandit SV, Rivolta I, et al. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res. 2005;96(7):800–7.PubMedGoogle Scholar
  50. 50.
    Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299(5604):251–4.PubMedGoogle Scholar
  51. 51.
    Xia M, Jin Q, Bendahhou S, et al. A Kir2.1 gain-of-function mutation underlies familial atrial fibrillation. Biochem Biophys Res Commun. 2005;332(4):1012–9.PubMedGoogle Scholar
  52. 52.
    Yang Y, Xia M, Jin Q, et al. Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation. Am J Hum Genet. 2004;75(5):899–905.PubMedGoogle Scholar
  53. 53.
    Frischmeyer PA, Vvan HA, O’Donnell K, Guerrerio AL, Parker R, Dietz HC. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science. 2002;295(5563):2258–61.PubMedGoogle Scholar
  54. 54.
    Gong Q, Zhang L, Vincent GM, Horne BD, Zhou Z. Nonsense mutations in hERG cause a decrease in mutant mRNA transcripts by nonsense-mediated mRNA decay in human long-QT syndrome. Circulation. 2007;116(1):17–24.PubMedGoogle Scholar
  55. 55.
    Westenskow P, Splawski I, Timothy KW, Keating MT, Sanguinetti MC. Compound mutations: a common cause of severe long-QT syndrome. Circulation. 2004;109(15):1834–41.PubMedGoogle Scholar
  56. 56.
    Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM. Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation. 1996;94(8):1996–2012.PubMedGoogle Scholar
  57. 57.
    Priori SG, Napolitano C, Schwartz PJ. Low penetrance in the long-QT syndrome: clinical impact. Circulation. 1999;99(4):529–33.PubMedGoogle Scholar
  58. 58.
    Napolitano C, Schwartz PJ, Brown AM, et al. Evidence for a cardiac ion channel mutation underlying drug-induced QT prolongation and life-threatening arrhythmias. J Cardiovasc Electrophysiol. 2000;11(6):691–6.PubMedGoogle Scholar
  59. 59.
    Sesti F, Abbott GW, Wei J, et al. A common polymorphism associated with antibiotic-induced cardiac arrhythmia. Proc Natl Acad Sci U S A. 2000;97(19):10613–8.PubMedGoogle Scholar
  60. 60.
    Splawski I, Timothy KW, Tateyama M, et al. Variant of SCN5A sodium channel implicated in risk of cardiac arrhythmia. Science. 2002;297(5585):1333–6.PubMedGoogle Scholar
  61. 61.
    Chevalier P, Rodriguez C, Bontemps L, et al. Non-invasive testing of acquired long QT syndrome: evidence for multiple arrhythmogenic substrates. Cardiovasc Res. 2001;50(2):386–98.PubMedGoogle Scholar
  62. 62.
    Itoh H, Sakaguchi T, Ding WG, et al. Latent genetic backgrounds and molecular pathogenesis in drug-induced long-QT syndrome. Circ Arrhythm Electrophysiol. 2009;2(5):511–23.PubMedGoogle Scholar
  63. 63.
    Huang L, Bitner-Glindzicz M, Tranebjaerg L, Tinker A. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res. 2001;51(4):670–80.PubMedGoogle Scholar
  64. 64.
    Roden DM, George Jr AL. The cardiac ion channels: relevance to management of arrhythmias. Annu Rev Med. 1996;47:135–48.PubMedGoogle Scholar
  65. 65.
    Pfeufer A, Sanna S, Arking DE, et al. Common variants at ten loci modulate the QT interval duration in the QTSCD Study. Nat Genet. 2009;41(4):407–14.PubMedGoogle Scholar
  66. 66.
    Newton-Cheh C, Eijgelsheim M, Rice KM, et al. Common variants at ten loci influence QT interval duration in the QTGEN Study. Nat Genet. 2009;41(4):399–406.PubMedGoogle Scholar
  67. 67.
    Chang KC, Barth AS, Sasano T, et al. CAPON modulates cardiac repolarization via neuronal nitric oxide synthase signaling in the heart. Proc Natl Acad Sci U S A. 2008;105(11):4477–82.PubMedGoogle Scholar
  68. 68.
    Herskowitz I. Functional inactivation of genes by dominant negative mutations. Nature. 1987;329(6136):219–22.PubMedGoogle Scholar
  69. 69.
    Moss AJ, Kass RS. Long QT syndrome: from channels to cardiac arrhythmias. J Clin Invest. 2005;115(8):2018–24.PubMedGoogle Scholar
  70. 70.
    Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005;85(4):1205–53.PubMedGoogle Scholar
  71. 71.
    Franqueza L, Lin M, Splawski I, Keating MT, Sanguinetti MC. Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits. J Biol Chem. 1999;274(30):21063–70.PubMedGoogle Scholar
  72. 72.
    Wang Z, Tristani Firouzi M, Xu Q, Lin M, Keating MT, Sanguinetti MC. Functional effects of mutations in KvLQT1 that cause long QT syndrome. J Cardiovasc Electrophysiol. 1999;10(6):817–26.PubMedGoogle Scholar
  73. 73.
    Yang T, Chung SK, Zhang W, et al. Biophysical properties of 9 KCNQ1 mutations associated with long-QT syndrome. Circ Arrhythm Electrophysiol. 2009;2(4):417–26.PubMedGoogle Scholar
  74. 74.
    Bendahhou S, Fournier E, Sternberg D, et al. In vivo and in vitro functional characterization of Andersen’s syndrome mutations. J Physiol. 2005;565(Pt 3):731–41.PubMedGoogle Scholar
  75. 75.
    Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE. Alterations in conserved Kir channel-PIP2 interactions underlie channelopathies. Neuron. 2002;34(6):933–44.PubMedGoogle Scholar
  76. 76.
    Dahimene S, Alcolea S, Naud P, et al. The N-terminal juxtamembranous domain of KCNQ1 is critical for channel surface expression – implications in the Romano-Ward LQT1 syndrome. Circ Res. 2006;99(10):1076–83.PubMedGoogle Scholar
  77. 77.
    Ficker E, Dennis AT, Obejero-Paz CA, Castaldo P, Taglialatela M, Brown AM. Retention in the endoplasmic reticulum as a mechanism of dominant-negative current suppression in human long QT syndrome. J Mol Cell Cardiol. 2000;32(12):2327–37.PubMedGoogle Scholar
  78. 78.
    Ficker E, Thomas D, Viswanathan PC, et al. Novel characteristics of a misprocessed mutant HERG channel linked to hereditary long QT syndrome. Am J Physiol Heart Circ Physiol. 2000;279(4):H1748–56.PubMedGoogle Scholar
  79. 79.
    Gouas L, Bellocq C, Berthet M, et al. New KCNQ1 mutations leading to haploinsufficiency in a general population – defective trafficking of a KvLQT1 mutant. Cardiovasc Res. 2004;63(1):60–8.PubMedGoogle Scholar
  80. 80.
    Sato A, Arimura T, Makita N, et al. Novel mechanisms of trafficking defect caused by KCNQ1 mutations found in long QT syndrome. J Biol Chem. 2009;284(50):35122–33.PubMedGoogle Scholar
  81. 81.
    Schmitt N, Schwarz M, Peretz A, Abitbol I, Attali B, Pongs O. A recessive C-terminal Jervell and Lange-Nielsen mutation of the KCNQ1 channel impairs subunit assembly. EMBO J. 2000;19(3):332–40.PubMedGoogle Scholar
  82. 82.
    Wilson AJ, Quinn KV, Graves FM, Bitner-Glindzicz M, Tinker A. Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1). Cardiovasc Res. 2005;67(3):476–86.PubMedGoogle Scholar
  83. 83.
    Yamashita F, Horie M, Kubota T, et al. Characterization and subcellular localization of KCNQ1 with a heterozygous mutation in the C terminus. J Mol Cell Cardiol. 2001;33(2):197–207.PubMedGoogle Scholar
  84. 84.
    Zhou Z, Gong Q, Epstein ML, January CT. HERG channel dysfunction in human long QT syndrome. Intracellular transport and functional defects. J Biol Chem. 1998;273(33):21061–6.PubMedGoogle Scholar
  85. 85.
    Anderson CL, Delisle BP, Anson BD, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113(3):365–73.PubMedGoogle Scholar
  86. 86.
    Pan N, Sun J, Lv CX, Li H, Ding JP. A hydrophobicity-dependent motif responsible for surface expression of cardiac potassium channel. Cell Signal. 2009;21(2):349–55.PubMedGoogle Scholar
  87. 87.
    Akhavan A, Atanasiu R, Shrier A. Identification of a COOH-terminal segment involved in maturation and stability of human ether-a-go-go-related gene potassium channels. J Biol Chem. 2003;278(41):40105–12.PubMedGoogle Scholar
  88. 88.
    Gong Q, Keeney DR, Robinson JC, Zhou Z. Defective assembly and trafficking of mutant HERG channels with C-terminal truncations in long QT syndrome. J Mol Cell Cardiol. 2004;37(6):1225–33.PubMedGoogle Scholar
  89. 89.
    Kupershmidt S, Yang T, Chanthaphaychith S, Wang Z, Towbin JA, Roden DM. Defective human Ether-à-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus. J Biol Chem. 2002;277(30):27442–8.PubMedGoogle Scholar
  90. 90.
    Wiener R, Haitin Y, Shamgar L, et al. The KCNQ1 (Kv7.1) COOH terminus, a multitiered scaffold for subunit assembly and protein interaction. J Biol Chem. 2008;283(9):5815–30.PubMedGoogle Scholar
  91. 91.
    Kanki H, Kupershmidt S, Yang T, Wells S, Roden DM. A structural requirement for processing the cardiac K+ channel KCNQ1. J Biol Chem. 2004;279(32):33976–83.PubMedGoogle Scholar
  92. 92.
    Splawski I, TristaniFirouzi M, Lehmann MH, Sanguinetti MC, Keating MT. Mutations in the hminK gene cause long QT syndrome and suppress I-Ks function. Nat Genet. 1997;17(3):338–40.PubMedGoogle Scholar
  93. 93.
    Bianchi L, Shen Z, Dennis AT, et al. Cellular dysfunction of LQT5-minK mutants: abnormalities of IKs, IKr and trafficking in long QT syndrome. Hum Mol Genet. 1999;8(8):1499–507.PubMedGoogle Scholar
  94. 94.
    Harmer SC, Wilson AJ, Aldridge R, Tinker A. Mechanisms of disease pathogenesis in long QT syndrome type 5. Am J Physiol Cell Physiol. 2010;298(2):C263–73.PubMedGoogle Scholar
  95. 95.
    Krumerman A, Gao X, Bian JS, Melman YF, Kagan A, McDonald TV. An LQT mutant minK alters KvLQT1 trafficking. Am J Physiol Cell Physiol. 2004;286(6):C1453–63.PubMedGoogle Scholar
  96. 96.
    Abbott GW, Xu X, Roepke TK. Impact of ancillary subunits on ventricular repolarization. J Electrocardiol. 2007;40(6 Suppl):S42–6.PubMedGoogle Scholar
  97. 97.
    Aridor M. Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases. Adv Drug Deliv Rev. 2007;59(8):759–81.PubMedGoogle Scholar
  98. 98.
    Ficker E, Dennis AT, Wang L, Brown AM. Role of the cytosolic chaperones Hsp70 and Hsp90 in maturation of the cardiac potassium channel HERG. Circ Res. 2003;92(12):e87–100.PubMedGoogle Scholar
  99. 99.
    Walker VE, Wong MJ, Atanasiu R, Hantouche C, Young JC, Shrier A. Hsp40 chaperones promote degradation of the HERG potassium channel. J Biol Chem. 2010;285(5):3319–29.PubMedGoogle Scholar
  100. 100.
    Walker VE, Atanasiu R, Lam H, Shrier A. Co-chaperone FKBP38 promotes HERG trafficking. J Biol Chem. 2007;282(32):23509–16.PubMedGoogle Scholar
  101. 101.
    Ghosh S, Nunziato DA, Pitt GS. KCNQ1 assembly and function is blocked by long-QT syndrome mutations that disrupt interaction with calmodulin. Circ Res. 2006;98(8):1048–54.PubMedGoogle Scholar
  102. 102.
    Shamgar L, Ma L, Schmitt N, et al. Calmodulin is essential for cardiac IKS channel gating and assembly: impaired function in long-QT mutations. Circ Res. 2006;98(8):1055–63.PubMedGoogle Scholar
  103. 103.
    Gong Q, Keeney DR, Molinari M, Zhou Z. Degradation of trafficking-defective long QT syndrome type II mutant channels by the ubiquitin-proteasome pathway. J Biol Chem. 2005;280(19):19419–25.PubMedGoogle Scholar
  104. 104.
    Peroz D, Dahimene S, Baro I, Loussouarn G, Merot J. LQT1-associated mutations increase KCNQ1 proteasomal degradation independently of Derlin-1. J Biol Chem. 2009;284(8):5250–6.PubMedGoogle Scholar
  105. 105.
    Roti EC, Myers CD, Ayers RA, et al. Interaction with GM130 during HERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether-à-go-go-Related Gene. J Biol Chem. 2002;277(49):47779–85.PubMedGoogle Scholar
  106. 106.
    Fortune ES, Chacron MJ. From molecules to behavior: organismal-level regulation of ion channel trafficking. PLoS Biol. 2009;7(9):e1000211.PubMedGoogle Scholar
  107. 107.
    Jespersen T, Membrez M, Nicolas CS, et al. The KCNQ1 potassium channel is down-regulated by ubiquitylating enzymes of the Nedd4/Nedd4-like family. Cardiovasc Res. 2007;74(1):64–74.PubMedGoogle Scholar
  108. 108.
    Guo J, Massaeli H, Xu J, et al. Extracellular K+ concentration controls cell surface density of IKr in rabbit hearts and of the HERG channel in human cell lines. J Clin Invest. 2009;119(9):2745–57.PubMedGoogle Scholar
  109. 109.
    Robertson GA. Endocytic control of ion channel density as a target for cardiovascular disease. J Clin Invest. 2009;119(9):2531–4.PubMedGoogle Scholar
  110. 110.
    Kupershmidt S, Yang IC, Sutherland M, et al. Cardiac-enriched LIM domain protein fhl2 is required to generate I(Ks) in a heterologous system. Cardiovasc Res. 2002;56(1):93–103.PubMedGoogle Scholar
  111. 111.
    Lin J, Lin S, Yu X, et al. The four and a half LIM domain protein 2 interacts with and regulates the HERG channel. FEBS J. 2008;275(18):4531–9.PubMedGoogle Scholar
  112. 112.
    Seebohm G, Strutz-Seebohm N, Birkin R, et al. Regulation of endocytic recycling of KCNQ1/KCNE1 potassium channels. Circ Res. 2007;100(5):686–92.PubMedGoogle Scholar
  113. 113.
    Busjahn A, Seebohm G, Maier G, et al. Association of the serum and glucocorticoid regulated kinase (sgk1) gene with QT interval. Cell Physiol Biochem. 2004;14(3):135–42.PubMedGoogle Scholar
  114. 114.
    Wible BA, Hawryluk P, Ficker E, Kuryshev YA, Kirsch G, Brown AM. HERG-Lite: a novel comprehensive high-throughput screen for drug-induced hERG risk. J Pharmacol Toxicol Methods. 2005;52(1):136–45.PubMedGoogle Scholar
  115. 115.
    Guo J, Massaeli H, Li W, et al. Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. J Pharmacol Exp Ther. 2007;321(3):911–20.PubMedGoogle Scholar
  116. 116.
    Kuryshev YA, Ficker E, Wang L, et al. Pentamidine-induced long QT syndrome and block of hERG trafficking. J Pharmacol Exp Ther. 2005;312(1):316–23.PubMedGoogle Scholar
  117. 117.
    Mitcheson JS, Chen J, Lin M, Culberson C, Sanguinetti MC. A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci U S A. 2000;97(22):12329–33.PubMedGoogle Scholar
  118. 118.
    Stansfeld PJ, Gedeck P, Gosling M, Cox B, Mitcheson JS, Sutcliffe MJ. Drug block of the hERG potassium channel: insight from modeling. Proteins. 2007;68(2):568–80.PubMedGoogle Scholar
  119. 119.
    Denning GM, Anderson MP, Amara JF, Marshall J, Smith AE, Welsh MJ. Processing of mutant cystic fibrosis transmembrane conductance regulator is temperature-sensitive. Nature. 1992;358(6389):761–4.PubMedGoogle Scholar
  120. 120.
    Furutani M, Trudeau MC, Hagiwara N, et al. Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. Circulation. 1999;99(17):2290–4.PubMedGoogle Scholar
  121. 121.
    Zhou Z, Gong Q, January CT. Correction of defective protein trafficking of a mutant HERG potassium channel in human long QT syndrome. Pharmacological and temperature effects. J Biol Chem. 1999;274(44):31123–6.PubMedGoogle Scholar
  122. 122.
    Ficker E, Obejero-Paz CA, Zhao S, Brown AM. The binding site for channel blockers that rescue misprocessed human long QT syndrome type 2 ether-a-gogo-related gene (HERG) mutations. J Biol Chem. 2002;277(7):4989–98.PubMedGoogle Scholar
  123. 123.
    Compton SJ, Lux RL, Ramsey MR, et al. Genetically defined therapy of inherited long-QT syndrome. Correction of abnormal repolarization by potassium. Circulation. 1996;94(5):1018–22.PubMedGoogle Scholar
  124. 124.
    Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008;372(9640):719–27.PubMedGoogle Scholar
  125. 125.
    Abitbol I, Peretz A, Lerche C, Busch AE, Attali B. Stilbenes and fenamates rescue the loss of I(KS) channel function induced by an LQT5 mutation and other IsK mutants. EMBO J. 1999;18(15):4137–48.PubMedGoogle Scholar
  126. 126.
    Schwartz PJ, Priori SG, Locati EH, 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. Circulation. 1995;92(12):3381–6.PubMedGoogle Scholar
  127. 127.
    Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: pharmacological treatment. J Am Coll Cardiol. 2004;43(8):1494–9.PubMedGoogle Scholar
  128. 128.
    Kaufman ES, Ficker E. Is restoration of intracellular trafficking clinically feasible in the long QT syndrome?: The example of HERG mutations. J Cardiovasc Electrophysiol. 2003;14(3):320–2.PubMedGoogle Scholar
  129. 129.
    Rajamani S, Anderson CL, Anson BD, January CT. Pharmacological rescue of human K(+) channel long-QT2 mutations: human ether-a-go-go-related gene rescue without block. Circulation. 2002;105(24):2830–5.PubMedGoogle Scholar
  130. 130.
    Delisle BP, Anderson CL, Balijepalli RC, Anson BD, Kamp TJ, January CT. Thapsigargin selectively rescues the trafficking defective LQT2 channels G601S and F805C. J Biol Chem. 2003;278(37):35749–54.PubMedGoogle Scholar

Copyright information

© Springer-Verlag London Limited 2012

Authors and Affiliations

  1. 1.Department of MedicineUniversity College LondonLondonUK

Personalised recommendations