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The HERG K+ channel: progress in understanding the molecular basis of its unusual gating kinetics

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An Erratum to this article was published on 12 May 2004

Abstract

The HERG K+ channel has very unusual kinetic behaviour that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarisation as well as in preventing lethal ventricular arrhythmias. Extensive mutagenesis of the HERG K+ channel has allowed identification of which regions of the channel are important for the unusual kinetic behaviour of the channel. Furthermore, structural studies on scorpion toxins that potently inhibit HERG are beginning to provide clues as to the structural differences between HERG and other voltage-gated K+ channels.

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Fig. 1A–D.
Fig. 2A–C.
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Fig. 5A–B.

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Notes

  1. LQTS is a disorder of the electrical system in the heart characterised by a prolonged QT interval on the surface electrocardiogram (reviewed in Keating and Sanguinetti 2001). The duration of the QT interval is a measure of the time required for depolarisation and repolarisation of the heart. Prolongation of the QT interval significantly increases the risk of ventricular arrhythmias, and in particular an arrhythmia known as “torsade de pointes” which causes syncope (sudden loss of consciousness due to lack of blood flow to the brain) and, if it persists, sudden death.

  2. Channels may exist in one of three main forms, viz. closed, open or inactive. The transition from closed to open is referred to as activation, and the transition from open back to closed as deactivation. The inactive state refers to a conformation of the channel in which the activation gate is “open”; however, the channel is not able to conduct. There are multiple mechanisms by which inactivation may take place and these are described in more detail in Yellen (1998). Transitions into the inactive state are referred to as inactivation and the reverse process as recovery from inactivation.

  3. It should be noted that fully activated HERG K+ channels have a linear current–voltage relationship which can be revealed by triple pulse protocols designed to allow channels to recover from inactivation (see Smith et al. 1996). Thus HERG K+ channels are not true inward rectifiers

  4. There are now know to be at least six gene loci associated with congenital long QT syndrome, denoted LQTS1–6. LQTS1 is caused by mutations in KCNQ1 (encodes the alpha subunit of the slow component of the delayed rectifier K+ channel) on chromosome 11 (Wang et al. 1996). LQTS2 is caused by mutations in HERG on chromosome 7 (Curran et al. 1995). LQTS3 is caused by mutations in SCN5a (encodes the alpha subunit of the cardiac Na+ channel) on chromosome 3 (Wang et al. 1995). LQTS4 is caused by mutations in ankyrin B on chromosome 4 (Mohler et al. 2003). LQTS5 is caused by mutations in KCNE1 (encodes the beta subunit of the slow component of the delayed rectifier K+ channel) (Splawski et al. 1997). LQTS6 is caused by mutations in KCNE2 (encodes a K+ channel beta subunit that can associate with multiple alpha subunits including HERG and KCNQ1) (Abbott et al. 1999).

References

  • Abbott GW et al (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175–187

    CAS  PubMed  Google Scholar 

  • Anumonwo JM et al (1999) Proton and zinc effects on HERG currents. Biophys J 77:282–298

    CAS  PubMed  Google Scholar 

  • Aydar E, Palmer C (2001) Functional characterization of the C-terminus of the human ether-a-go-go-related gene K(+) channel (HERG). J Physiol 534:1–14

    CAS  PubMed  Google Scholar 

  • Baukrowitz T, Yellen G (1995) Modulation of K+ current by frequency and external [K+]: a tale of two inactivation mechanisms. Neuron 15:951–960

    CAS  PubMed  Google Scholar 

  • Chen J et al (1999) Long QT syndrome-associated mutations in the Per-Arnt-Sim (PAS) domain of HERG potassium channels accelerate channel deactivation. J Biol Chem 274:10113–10118

    CAS  PubMed  Google Scholar 

  • Corona M et al (2002) A large number of novel Ergtoxin-like genes and ERG K+-channels blocking peptides from scorpions of the genus Centruroides. FEBS Lett 532:121–126

    Article  CAS  PubMed  Google Scholar 

  • Cui J et al (2001) Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2. J Biol Chem 276:17244–17251

    CAS  PubMed  Google Scholar 

  • Curran ME et al (1995) A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Cell 80:795–803

    CAS  PubMed  Google Scholar 

  • Doyle DA et al (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280:69–77

    CAS  PubMed  Google Scholar 

  • Emmi A et al (2000) Do glia have heart? Expression and functional role for ether-a-go-go currents in hippocampal astrocytes. J Neurosci 20:3915–3925

    CAS  PubMed  Google Scholar 

  • Fan JS et al (1999) Effects of outer mouth mutations on hERG channel function: a comparison with similar mutations in the Shaker channel. Biophys J 76:3128–3140

    CAS  PubMed  Google Scholar 

  • Ficker E et al (1998). Molecular determinants of dofetilide block of HERG K+ channels. Circ Res 82:386–395

    CAS  PubMed  Google Scholar 

  • Fozzard HA (2000) Channel-specific therapy of cardiac arrhythmias in our time? J Cardiovasc Electrophysiol 11:369–370

    Google Scholar 

  • Gross A, MacKinnon R (1996) Agitoxin footprinting the shaker potassium channel pore. Neuron 16:399–406

    CAS  PubMed  Google Scholar 

  • Gullo F et al (2003) ERG K+ channel blockade enhances firing and epinephrine secretion in rat chromaffin cells: the missing link to LQT2-related sudden death? FASEB J 17:330–332

    Google Scholar 

  • Herzberg IM et al (1998) Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels. J Physiol 511:3–14

    CAS  PubMed  Google Scholar 

  • Hidalgo P, MacKinnon R (1995) Revealing the architecture of a K+ channel pore through mutant cycles with a peptide inhibitor. Science 268:307–310

    CAS  PubMed  Google Scholar 

  • Hoshi T et al (1991) Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region. Neuron 7:547–556

    CAS  PubMed  Google Scholar 

  • Jiang M et al (1999) Mechanism for the effects of extracellular acidification on HERG-channel function. Am J Physiol 277:H1283–H1292

    PubMed  Google Scholar 

  • Jiang Y et al (2002) The open pore conformation of potassium channels. Nature 417:523–526

    Article  CAS  PubMed  Google Scholar 

  • Jiang Y et al (2003) The principle of gating charge movement in a voltage-dependent K+ channel. Nature 423:42-48

    Article  CAS  PubMed  Google Scholar 

  • Keating MT, Sanguinetti MC (2001). Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569–580

    CAS  PubMed  Google Scholar 

  • Kiehn J et al (1999). Pathways of HERG inactivation. Am J Physiol 277:H199–H210

    CAS  PubMed  Google Scholar 

  • Koradi, R., Billeter, M., and Wuthrich, K. (1996) MOLMOL: a program for display and analysis of macromolecular structures. J Mol Graph 14:51–55

    CAS  Google Scholar 

  • Korolkova YV et al (2002) New binding site on common molecular scaffold provides HERG channel specificity of scorpion toxin BeKm-1. J Biol Chem 277:43104–43109

    Article  CAS  PubMed  Google Scholar 

  • Korolokova YV et al (2003) Probing the unique structure of HERG’s outer vestibule using mutant cycle analysis. Biophys J 84:8a (abstract)

    Google Scholar 

  • Kupershmidt S et al (2002). Defective human Ether-a-go-go-related gene trafficking linked to an endoplasmic reticulum retention signal in the C terminus. J Biol Chem 277:27442–27448

    Article  CAS  PubMed  Google Scholar 

  • Lanigan MD et al (2002) Mutating a critical lysine in ShK toxin alters its binding configuration in the pore-vestibule region of the voltage-gated potassium channel, Kv1.3.Biochemistry. 41:11963–11971

    Google Scholar 

  • Liu J et al (2002) Structural and functional role of the extracellular S5-P linker in the HERG potassium channel J Gen Physiol 120:723–737

    Google Scholar 

  • Liu J et al (2003) Negative charges in the transmembrane domains of the HERG K channel are involved in the activation- and deactivation-gating processes. J Gen Physiol 121:599-614

    Article  CAS  PubMed  Google Scholar 

  • Loots E, Isacoff EY (1998) Protein rearrangements underlying slow inactivation of the Shaker K+ channel. J Gen Physiol. 112:377–389

    Google Scholar 

  • Lu Y et al (2001) Effects of premature stimulation on HERG K(+) channels. J Physiol. 537:843–851

    Google Scholar 

  • Meyer R, Heinemann SH (1997) Temperature and pressure dependence of Shaker K+ channel N- and C-type inactivation. Eur Biophys J. 26:433–445

    Google Scholar 

  • Mitcheson JS et al (2001) A structural basis for drug-induced long QT syndrome. Proc Natl Acad Sci USA 97:12329–12333

    Article  Google Scholar 

  • Mohler PJ et al (2003) Ankyrin-B mutation causes type 4 long-QT cardiac arrhythmia and sudden cardiac death. Nature 421:634–639

    Article  CAS  PubMed  Google Scholar 

  • Morais Cabral JH et al (1998) Crystal structure and functional analysis of the HERG potassium channel N-terminus: a eukaryotic PAS domain. Cell 95:649–655

    PubMed  Google Scholar 

  • Nakajima T et al (1998) Novel mechanism of HERG current suppression in LQT2: shift in voltage dependence of HERG inactivation. Circ Res 83:415–422

    CAS  PubMed  Google Scholar 

  • Pardo-Lopez L et al (2002) Mapping the binding site of a human ether-a-go-go-related gene-specific peptide toxin (ErgTx) to the channel’s outer vestibule. J Biol Chem 277:16403–16411

    Article  CAS  PubMed  Google Scholar 

  • Perozo E et al (1993). Gating currents from a nonconducting mutant reveal open-closed conformations in Shaker K+ channels. Neuron 11:353–358

    CAS  PubMed  Google Scholar 

  • Piper et al (2003) HERG channel gating currents. Biophys J 84:543a (abstract)

    Google Scholar 

  • Ponting CP, Aravind L (1997) PAS: a multifunctional domain family comes to light. Curr Biol. 7:R674–R677

    Google Scholar 

  • Proks P et al (2001) Mutations within the P-loop of Kir6.2 modulate the intraburst kinetics of the ATP-sensitive potassium channel. J Gen Physiol 118:341–353

    Article  CAS  PubMed  Google Scholar 

  • Ranganathan R et al (1996) Spatial localization of the K+ channel selectivity filter by mutant cycle-based structure analysis. Neuron 16:131–139

    CAS  PubMed  Google Scholar 

  • Rosati B et al (2000) Glucose- and arginine-induced insulin secretion by human pancreatic beta-cells: the role of HERG K(+) channels in firing and release. FASEB J 14:2601–2610

    Article  CAS  PubMed  Google Scholar 

  • Sanguinetti MC, Xu QP (1999) Mutations of the S4-S5 linker alter activation properties of HERG potassium channels expressed in Xenopus oocytes. J Physiol 514:667–675

    CAS  PubMed  Google Scholar 

  • Sanguinetti MC et al (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81:299–307

    PubMed  Google Scholar 

  • Schonherr R, Heinemann SH (1996) Molecular determinants for activation and inactivation of HERG, a human inward rectifier potassium channel. J Physiol 493:635–642

    PubMed  Google Scholar 

  • Seoh SA et al (1996) Voltage-sensing residues in the S2 and S4 segments of the Shaker K+ channel. Neuron 16:1159–1167

    CAS  PubMed  Google Scholar 

  • Shoeb F et al (2003) Cloning and functional characterization of the smooth muscle ether-a-go-go-related gene K+ channel. Potential role of a conserved amino acid substitution in the S4 region. J Biol Chem 278:2503–2514

    Article  CAS  PubMed  Google Scholar 

  • Smith PL, Yellen G (2002) Fast and slow voltage sensor movements in HERG potassium channels. J Gen Physiol 119:275–293

    Article  CAS  PubMed  Google Scholar 

  • Smith PL et al (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379:833–836

    Google Scholar 

  • Spector PS et al (1996) Fast inactivation causes rectification of the IKr channel. J Gen Physiol 107:611–619

    CAS  PubMed  Google Scholar 

  • Splawski I et al (1997) Mutations in the hminK gene cause long QT syndrome and suppress IKs function. Nat Genet 17:338–340

    CAS  PubMed  Google Scholar 

  • Splawski I et al (2000) Spectrum of mutations in long-QT syndrome genes. KVLQT1, HERG, SCN5A, KCNE1, andKCNE2. Circulation 102:1178–1185

    CAS  PubMed  Google Scholar 

  • Terlau H et al (1997). Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4 segment. J Physiol 502:537–543

    CAS  PubMed  Google Scholar 

  • Thompson JD et al (1994) CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 22:4673–4680

    PubMed  Google Scholar 

  • Torres et al (2003) Solution structure of CnErg1 (Ergtoxin), a HERG specific scorpion toxin. FEBS Lett 539:138–142

    Article  PubMed  Google Scholar 

  • Tristani-Firouzi M et al (2002) Interactions between S4–S5 linker and S6 transmembrane domain modulate gating of HERG K+ channels. J Biol Chem 277:18994–19000

    Article  CAS  PubMed  Google Scholar 

  • Trudeau MC et al (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269:92–95

    Google Scholar 

  • Tseng GN (2001) I(Kr): the hERG channel. J Mol Cell Cardiol 33:835–849

    Article  CAS  PubMed  Google Scholar 

  • Vandenberg JI et al (2001) HERG K+ channels: friend and foe. Trends Pharmacol Sci 22:240–246

    Article  CAS  PubMed  Google Scholar 

  • Wang J et al (1998) Regulation of deactivation by an amino terminal domain in human ether-a-go-go-related gene potassium channels. J Gen Physiol 112:637–647

    CAS  PubMed  Google Scholar 

  • Wang J et al (2000) Dynamic control of deactivation gating by a soluble amino-terminal domain in HERG K(+) channels. J Gen Physiol 115:749–758

    CAS  PubMed  Google Scholar 

  • Wang Q et al (1995)SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805–811

    CAS  PubMed  Google Scholar 

  • Wang Q et al (1996) Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat Genet 12:17–23

    PubMed  Google Scholar 

  • Wang S et al (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J Physiol 502:45–60

    CAS  PubMed  Google Scholar 

  • Warmke JW, Ganetzky B (1994) A family of potassium channel genes related to eag in Drosophila and mammals.Proc Natl Acad Sci USA 91:3438–3442

    CAS  PubMed  Google Scholar 

  • Yellen G (1998) The moving parts of voltage-gated ion channels. Q Rev Biophys 31:239–295

    CAS  PubMed  Google Scholar 

  • Yifrach O, MacKinnon R (2002) Energetics of pore opening in a voltage-gated K(+) channel. Cell 111(2):231–239

    CAS  PubMed  Google Scholar 

  • Zhou Z et al (1998) Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys J 74:230–241

    CAS  PubMed  Google Scholar 

  • Zou A et al (1998) A mutation in the pore region of HERG K+ channels expressed in Xenopus oocytes reduces rectification by shifting the voltage dependence of inactivation. J Physiol 509:129–137

    CAS  PubMed  Google Scholar 

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Acknowledgements

JIV is a NH&MRC Career Development Fellow. PWK is an ARC Principal Research Fellow. Research in the authors’ laboratories is supported by the NH&MRC (JIV, TJC), National Heart Foundation of Australia (JIV, TJC) and the Australian Research Council (PWK).

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Authors and Affiliations

  1. Victor Chang Cardiac Research Institute, Level 9, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia

    Jamie I. Vandenberg & Terence J. Campbell

  2. Department of Medicine, St. Vincent’s Hospital, University of New South Wales, Darlinghurst, NSW, 2010, Australia

    Jamie I. Vandenberg & Terence J. Campbell

  3. School of Molecular and Microbial Biosciences, University of Sydney, Sydney, NSW, 2006, Australia

    Allan M. Torres & Philip W. Kuchel

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  1. Jamie I. Vandenberg
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  2. Allan M. Torres
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Correspondence to Jamie I. Vandenberg.

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This paper was submitted as a record of the 2002 Australien Biophysical Society.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00249-004-0419-y

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Vandenberg, J.I., Torres, A.M., Campbell, T.J. et al. The HERG K+ channel: progress in understanding the molecular basis of its unusual gating kinetics. Eur Biophys J 33, 89–97 (2004). https://doi.org/10.1007/s00249-003-0338-3

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