Skip to main content
SpringerLink
Log in
Book cover

Electrical Diseases of the Heart pp 233–244Cite as

K+ Channelopathies (IKs, IKr, and Ito)

  • Chapter
  • First Online:

  • 3203 Accesses

Abstract

Voltage gated K+ channels are comprised of a pore-forming α-subunit and one or more accessory subunits and allow for K+ ions to flow along their electrochemical gradient, typically out of the cell, in response to changes in membrane potential. Voltage-gated K+ channels act to help set the plateau potential in cardiac cells as well as to repolarize the membrane during an action potential. In cardiac myocytes, they are the primary class of channels responsible for controlling the duration of the action potential, alterations in which can have profound arrhythmic effects. Defects in K+ channel function have been linked to a number of heritable and acquired conditions leading to arrhythmia in affected patients. As we continue to characterize channel function biophysically, our mechanistic understanding of these conditions grows. Hopefully, this will continue to lead to novel therapeutic strategies not only for the relatively rare inherited channelopathies, but more widespread arrhythmias commonly encountered in clinical practice.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Cole KS. Mostly membranes (Kenneth S. Cole). Annu Rev Physiol. 1979;41:1–24.

    Article  PubMed  CAS  Google Scholar 

  2. Hodgkin AL, Huxley AF. Propagation of electrical signals along giant nerve fibers. Proc R Soc Lond B Biol Sci. 1952;140:177–83.

    Article  PubMed  CAS  Google Scholar 

  3. Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952;117:500–44.

    PubMed  CAS  Google Scholar 

  4. Hodgkin AL, Rushton WAH. The electrical constants of a crustacean nerve fiber. Proc R Soc Lond B Biol Sci. 1946;B133:444–79.

    Article  Google Scholar 

  5. Giraudat J, Devillers-Thiery A, Auffray C, Rougeon F, Changeux JP. Identification of a cDNA clone coding for the acetylcholine binding subunit of Torpedo marmorata acetylcholine receptor. EMBO J. 1982;1:713–7.

    PubMed  CAS  Google Scholar 

  6. Noda M, Takahashi H, Tanabe T, et al. Primary structure of alpha-subunit precursor of Torpedo californica acetylcholine receptor deduced from cDNA sequence. Nature. 1982;299:793–7.

    Article  PubMed  CAS  Google Scholar 

  7. 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;295:496–9.

    Article  PubMed  CAS  Google Scholar 

  8. Neher E, Sakmann B. Single-channel currents recorded from membrane of denervated frog muscle fibres. Nature. 1976;260:799–802.

    Article  PubMed  CAS  Google Scholar 

  9. Doyle DA, Morais Cabral J, Pfuetzner RA, et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science. 1998;280:69–77.

    Article  PubMed  CAS  Google Scholar 

  10. MacKinnon R. Potassium channels. FEBS Lett. 2003;555:62–5.

    Article  PubMed  CAS  Google Scholar 

  11. Clancy CE, Kass RS. Inherited and acquired vulnerability to ventricular arrhythmias: cardiac Na+ and K+ channels. Physiol Rev. 2005;85:33–47.

    Article  PubMed  CAS  Google Scholar 

  12. Sanguinetti MC, Tristani-Firouzi M. hERG potassium channels and cardiac arrhythmia. Nature. 2006;440:463–9.

    Article  PubMed  CAS  Google Scholar 

  13. Clancy CE, Kurokawa J, Tateyama M, Wehrens XH, Kass RS. K+ channel structure-activity relationships and mechanisms of drug-induced QT prolongation. Annu Rev Pharmacol Toxicol. 2003;43:441–61.

    Article  PubMed  CAS  Google Scholar 

  14. Jervell A, Lange-Nielsen F. Congenital deaf-­mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am Heart J. 1957;54:59–68.

    Article  PubMed  CAS  Google Scholar 

  15. Ward OC. A new familial cardiac syndrome in children. J Ir Med Assoc. 1964;54:103–6.

    PubMed  CAS  Google Scholar 

  16. 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;80:795–803.

    Article  PubMed  CAS  Google Scholar 

  17. Wang Q, Curran ME, Splawski I, et al. Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet. 1996;12:17–23.

    Article  PubMed  Google Scholar 

  18. Haverkamp W, Breithardt G, Camm AJ, et al. The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a policy conference of the European Society of Cardiology. Eur Heart J. 2000;21:1216–31.

    Article  PubMed  CAS  Google Scholar 

  19. Chen YH, Xu SJ, Bendahhou S, et al. KCNQ1 gain-of-function mutation in familial atrial fibrillation. Science. 2003;299:251–4.

    Article  PubMed  CAS  Google Scholar 

  20. Brugada R, Hong K, Dumaine R, et al. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004;109:30–5.

    Article  PubMed  CAS  Google Scholar 

  21. Nerbonne JM, Kass RS. Molecular physiology of cardiac repolarization. Physiol Rev. 2005;85:1205–53.

    Article  PubMed  CAS  Google Scholar 

  22. Long SB, Campbell EB, Mackinnon R. Crystal structure of a mammalian voltage-dependent Shaker family K+ channel. Science. 2005;309:897–903.

    Article  PubMed  CAS  Google Scholar 

  23. Mannuzzu LM, Moronne MM, Isacoff EY. Direct physical measure of conformational rearrangement underlying potassium channel gating. Science. 1996;271:213–6.

    Article  PubMed  CAS  Google Scholar 

  24. Yang N, George Jr AL, Horn R. Molecular basis of charge movement in voltage-gated sodium channels. Neuron. 1996;16:113–22.

    Article  PubMed  Google Scholar 

  25. Noble D, Tsien RW. Reconstruction of the repolarization process in cardiac Purkinje fibres based on voltage clamp measurements of membrane current. J Physiol. 1969;200:233–54.

    PubMed  CAS  Google Scholar 

  26. Noble D, Tsien RW. Outward membrane currents activated in the plateau range of potentials in cardiac Purkinje fibres. J Physiol. 1969;200:205–31.

    PubMed  CAS  Google Scholar 

  27. Horie M, Hayashi S, Kawai C. Two types of delayed rectifying K+ channels in atrial cells of guinea pig heart. Jpn J Physiol. 1990;40:479–90.

    Article  PubMed  CAS  Google Scholar 

  28. Sanguinetti MC, Jurkiewicz NK. Delayed rectifier outward K+ current is composed of two currents in guinea pig atrial cells. Am J Physiol. 1991;260:H393–9.

    PubMed  CAS  Google Scholar 

  29. Sanguinetti MC, Jurkiewicz NK. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier K+ currents. Pflugers Arch. 1992;420:180–6.

    Article  PubMed  CAS  Google Scholar 

  30. Xu H, Guo W, Nerbonne JM. Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. J Gen Physiol. 1999;113:661–78.

    Article  PubMed  CAS  Google Scholar 

  31. Splawski I, Shen J, Timothy KW, et al. Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Circulation. 2000;102:1178–85.

    Article  PubMed  CAS  Google Scholar 

  32. Chen Q, Zhang D, Gingell RL, et al. Homozygous deletion in KVLQT1 associated with Jervell and Lange-Nielsen syndrome. Circulation. 1999;99:1344–7.

    Article  PubMed  CAS  Google Scholar 

  33. 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;384:78–80.

    Article  PubMed  CAS  Google Scholar 

  34. 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;384:80–3.

    Article  PubMed  CAS  Google Scholar 

  35. 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;104:20990–5.

    Article  PubMed  CAS  Google Scholar 

  36. 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;91:3438–42.

    Article  PubMed  CAS  Google Scholar 

  37. Abbott GW, Goldstein SA. A superfamily of small potassium channel subunits: form and function of the MinK-related peptides (MiRPs). Q Rev Biophys. 1998;31:357–98.

    Article  PubMed  CAS  Google Scholar 

  38. Abbott GW, Sesti F, Splawski I, et al. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell. 1999;97:175–87.

    Article  PubMed  CAS  Google Scholar 

  39. 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;97:10613–8.

    Article  PubMed  CAS  Google Scholar 

  40. Amoros I, Jimenez-Jaimez J, Tercedor L, et al. Functional effects of a missense mutation in HERG associated with type 2 long QT syndrome. Heart Rhythm. 2011;8:463–70.

    Article  PubMed  Google Scholar 

  41. Smith JL, McBride CM, Nataraj PS, Bartos DC, January CT, Delisle BP. Trafficking-deficient hERG K channels linked to long QT syndrome are regulated by a microtubule-dependent quality control compartment in the ER. Am J Physiol Cell Physiol. 2011;301:C75–85.

    Article  PubMed  CAS  Google Scholar 

  42. Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic targets. Nat Rev Drug Discov. 2009;8:982–1001.

    Article  PubMed  CAS  Google Scholar 

  43. Perry M, Sanguinetti M, Mitcheson J. Revealing the structural basis of action of hERG potassium channel activators and blockers. J Physiol. 2010;588:3157–67.

    Article  PubMed  CAS  Google Scholar 

  44. Gussak I, Brugada P, Brugada J, et al. Idiopathic short QT interval: a new clinical syndrome? Cardiology. 2000;94:99–102.

    Article  PubMed  CAS  Google Scholar 

  45. Gaita F, Giustetto C, Bianchi F, et al. Short QT syndrome: a familial cause of sudden death. Circulation. 2003;108:965–70.

    Article  PubMed  Google Scholar 

  46. Bellocq C, van Ginneken AC, Bezzina CR, et al. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation. 2004;109:2394–7.

    Article  PubMed  Google Scholar 

  47. Nattel S. New ideas about atrial fibrillation 50 years on. Nature. 2002;415:219–26.

    Article  PubMed  CAS  Google Scholar 

  48. Cannon CP, Stecker EC. New options for stroke prevention in atrial fibrillation. Am J Manag Care. 2010;16:S291–7.

    PubMed  Google Scholar 

  49. Restier L, Cheng L, Sanguinetti MC. Mechanisms by which atrial fibrillation-associated mutations in the S1 domain of KCNQ1 slow deactivation of IKs channels. J Physiol. 2008;586:4179–91.

    Article  PubMed  CAS  Google Scholar 

  50. 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;75:899–905.

    Article  PubMed  CAS  Google Scholar 

  51. Tinel N, Diochot S, Borsotto M, Lazdunski M, Barhanin J. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. EMBO J. 2000;19:6326–30.

    Article  PubMed  CAS  Google Scholar 

  52. Giudicessi JR, Ye D, Tester DJ, et al. Transient outward current (I(to)) gain-of-function mutations in the KCND3-encoded Kv4.3 potassium channel and Brugada syndrome. Heart Rhythm. 2011;8:1024–32.

    Article  PubMed  Google Scholar 

  53. Delpon E, Cordeiro JM, Nunez L, et al. Functional effects of KCNE3 mutation and its role in the development of Brugada syndrome. Circ Arrhythm Electrophysiol. 2008;1:209–18.

    Article  PubMed  CAS  Google Scholar 

  54. Hill SL, Evangelista JK, Pizzi AM, Mobassaleh M, Fulton DR, Berul CI. Proarrhythmia associated with cisapride in children. Pediatrics. 1998;101:1053–6.

    Article  PubMed  CAS  Google Scholar 

  55. Perrin MJ, Subbiah RN, Vandenberg JI, Hill AP. Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction. Prog Biophys Mol Biol. 2008;98:137–48.

    Article  PubMed  CAS  Google Scholar 

  56. Gintant G. An evaluation of hERG current assay performance: translating preclinical safety studies to clinical QT prolongation. Pharmacol Ther. 2011;129:109–19.

    Article  PubMed  CAS  Google Scholar 

  57. Nakajo K, Ulbrich MH, Kubo Y, Isacoff EY. Stoichiometry of the KCNQ1 – KCNE1 ion channel complex. Proc Natl Acad Sci U S A. 2010;107:18862–7.

    Article  PubMed  CAS  Google Scholar 

  58. Wang K, Terrenoire C, Sampson K, et al. Biophysical properties of slow potassium channels in human embryonic stem cell derived cardiomyocytes implicate subunit stoichiometry. J Physiol. 2011;589:6093–104.

    Article  PubMed  CAS  Google Scholar 

  59. Huang ZM, Gold JI, Koch WJ. G protein-coupled receptor kinases in normal and failing myocardium. Front Biosci. 2011;17:3047–60.

    Google Scholar 

  60. Sampson KJ, Terrenoire C, Cervantes DO, Kaba RA, Peters NS, Kass RS. Adrenergic regulation of a key cardiac potassium channel can contribute to atrial fibrillation: evidence from an I Ks transgenic mouse. J Physiol. 2008;586:627–37.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY, USA

    Kevin J. Sampson PhD

  2. Department of Pharmacology, College of Physicians and Surgeons, Columbia University, P&S 7 – 401, 630 West 168th Street, New York, NY, 10032, USA

    Robert S. Kass PhD

Authors
  1. Kevin J. Sampson PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert S. Kass PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert S. Kass PhD .

Editor information

Editors and Affiliations

  1. , Department of Internal Medicine, UMDNJ-RWJ Medical School, Robert Wood Johnson Pl. 1, New Brunswick, 08903-0019, New Jersey, USA

    Ihor Gussak

  2. , Gordon K. Moe Scholar, Masonic Medical Research Laboratory, Bleecker Street, Utica, 13501-1787, New York, USA

    Charles Antzelevitch

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer-Verlag London

About this chapter

Cite this chapter

Sampson, K.J., Kass, R.S. (2013). K+ Channelopathies (IKs, IKr, and Ito). In: Gussak, I., Antzelevitch, C. (eds) Electrical Diseases of the Heart. Springer, London. https://doi.org/10.1007/978-1-4471-4881-4_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-4471-4881-4_14

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-4471-4880-7

  • Online ISBN: 978-1-4471-4881-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation