Skip to main content
SpringerLink
Log in

Functionally-distinct proton-binding in HERG suggests the presence of two binding sites

  • Original Article
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

HERG (Human ether-à-go-go-related gene) potassium channels are crucial for cardiac action potential repolarization. HERG channels are also found in neuronal and tumor cells. The effect of pH0 on HERG is of clinical significance because of changes in pH during myocardial ischemia, inflammation, and respiratory alkalosis. We present evidence for the presence of multiple proton binding sites in HERG. Extracellular protons bind rapidly and reversibly to affect both activation and deactivation. However, these effects occur in two distinct pH0 ranges. The deactivation rate has a pKa of 6.76±0.02 compared to pKa of 5.50±0.02 for changes in current suppression, which suggests the presence of at least two proton binding sites on HERG with functionally distinct properties.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sanguinetti, M. C., Jiang, C., Curran, M. E., and Keating, M. T. (1995) A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81, 299–307.

    Article  PubMed  CAS  Google Scholar 

  2. Trudeau, M. C., Warmke, J. W., Ganetzky, B., and Robertson, G. A. (1995) HERG, a human inward rectifier in the voltage-gated potassium channel family. Science 269, 92–95.

    Article  PubMed  CAS  Google Scholar 

  3. Warmke, J. W. and Ganetzky, B. (1994) A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Nat. Acad. Sci. USA 91, 3438–3442.

    Article  PubMed  CAS  Google Scholar 

  4. Janse, M. J. and Wit, A. L. (1989) Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol. Rev. 69, 1049–1169.

    PubMed  CAS  Google Scholar 

  5. Yan, G. X. and Kleber, A. G. (1992) Changes in extracellular and intracellular pH in ischemic rabbit papillary muscle. Circulation Research Circ. Res. 71, 460–470.

    PubMed  CAS  Google Scholar 

  6. Carmeliet, E. (1999) Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol. Rev. 79, 917–1017.

    PubMed  CAS  Google Scholar 

  7. Berube, J., Chahine, M., and Daleau, P. (1999) Modulation of HERG potassium channel properties by external pH. Pflug. Arch.—Eur. J. Physiol. 438, 419–422.

    Article  CAS  Google Scholar 

  8. Anumonwo, J. M., Horta, J., Delmar, M., Taffet, S. M., and Jalife, J. (1999) Proton and zinc effects on HERG currents. Biophys. J. 77, 282–298.

    PubMed  CAS  Google Scholar 

  9. Terai, T., Furukawa, T., Katayama, Y., and Hiraoka, M. (2000) Effects of external acidosis on HERG current expressed in Xenopus oocytes. J. Mol. Cell. Cardiol. 32, 11–21.

    Article  PubMed  CAS  Google Scholar 

  10. Jiang, M., Dun, W., and Tseng, G. N. (1999) Mechanism for the effects of extracellular acidification on HERG-channel function. Am. J. Physiol. 277, H1283-H1292.

    PubMed  CAS  Google Scholar 

  11. Jo, S. H., Youm, J. B., Kim, I., Lee, C. O., Earm, Y. E., and Ho, W. K. (1999) Blockade of HERG channels expressed in Xenopus oocytes by external H+. Pflug. Arch.—Eur. J. Physiol. 438, 23–29.

    Article  CAS  Google Scholar 

  12. Smith, P. L., Baukrowitz, T., and Yellen, G. (1996) The inward rectification mechanism of the HERG cardiac potassium channel. Nature 379, 833–836.

    Article  PubMed  CAS  Google Scholar 

  13. Wang, S., Morales, M. J., Liu, S., Strauss, H. C., and Rasmusson, R. L. (1996) Time, voltage and ionic concentration dependence of rectification of h-erg expressed in Xenopus oocytes. FEBS Letters 389, 167–173.

    Article  PubMed  CAS  Google Scholar 

  14. Spector, P. S., Curran, M. E., Zou, A., Keating, M. T., and Sanguinetti, M. C. (1996) Fast inactivation causes rectification of the IKr channel. J. Gen. Physiol. 107, 611–619.

    Article  PubMed  CAS  Google Scholar 

  15. Liu, S., Rasmusson, R. L., Campbell, D. L., Wang, S., and Strauss, H. C. (1996) Activation and inactivation kinetics of an E-4031-sensitive current from single ferret atrial myocytes. Biophys. J. 70, 2704–2715.

    PubMed  CAS  Google Scholar 

  16. Shibasaki, T. (1987) Conductance and kinetics of delayed rectifier potassium channels in nodal cells of the rabbit heart. J. Physiol. 387, 227–250.

    PubMed  CAS  Google Scholar 

  17. Gintant, G. A. (1996) Two components of delayed rectifier current in canine atrium and ventricle. Does IKs play a role in the reverse rate dependence of class III agents? Circ. Res. 78, 26–37.

    PubMed  CAS  Google Scholar 

  18. Wang, S., Liu, S., Morales, M. J., Strauss, H. C., and Rasmusson, R. L. (1997) A quantitative analysis of the activation and inactivation kinetics of HERG expressed in Xenopus oocytes. J. Physiol. 502, 45–60.

    Article  PubMed  CAS  Google Scholar 

  19. Kiehn, J., Lacerda, A. E., Wible, B., and Brown, A. M. (1996) Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide. Circulation 94, 2572–2579.

    PubMed  CAS  Google Scholar 

  20. Johnson, J. P. Jr, Balser, J. R., and Bennett, P. B. (1999) Enhancement of HERG K+ Currents by Cd2+ Destabilization of the Inactivated State Biophys. J. 77, 2534–2541.

    Article  PubMed  CAS  Google Scholar 

  21. Woodhull, A. M. (1973) Ionic blockage of sodium channels in nerve. J. Gen. Physiol. 61, 687–708.

    Article  PubMed  CAS  Google Scholar 

  22. Kiehn, J. (2000) Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends in Cardiovascular Medicine 10, 205–209.

    Article  PubMed  CAS  Google Scholar 

  23. Muraki, K., Imaizumi, Y., Watanabe, M., Habuchi, Y., and Giles, W. R. (1995) Delayed rectifier K+ current in rabbit atrial myocytes. J. Physiol. 269, H524-H532.

    CAS  Google Scholar 

  24. Sanguinetti, M. C., Curran, M. E., Spector, P. S., and Keating, M. T. (1996) Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc. Nat. Acad. Sci. USA 93, 2208–2212.

    Article  PubMed  CAS  Google Scholar 

  25. Vereecke, J. and Carmeliet, E. (2000) The effect of external pH on the delayed rectifying K+ current in cardiac ventricular myocytes. Plug. Arch.—Eur. J. Physiol. 439, 739–751.

    Article  CAS  Google Scholar 

  26. Jiang, Y., Ruta, V., Chen, J., Lee, A., and MacKinnon, R. (2003) The principle of gating charge movement in a voltage-dependent K+ channel. Nature 423, 42–48.

    Article  PubMed  CAS  Google Scholar 

  27. Kuo, A., Gulbis, J. M., Antcliff, J. F., Rahman, T., Lowe, E. D., Zimmer, J., et al. (2003) Crystal structure of the potassium channel KirBacl.1 in the closed state. Science 439, 739–751.

    Google Scholar 

  28. Li, X. Y., Bett, G. C. L., Jiang, X. J., Bondarenko, V. E., Morales, M. J., and Rasmusson, R. L. (2003) Regulation of N- and C-type inactivation by pH0 and potassium in normal and mutant Kv1.4 channels: Evidence for transmembrane communication. Am. J. Physiol. Heart Circ. Physiol. 284, H71-H80.

    PubMed  CAS  Google Scholar 

  29. Cuello, L. G., Romero, J. G., Cortes, D. M., and Perozo, E. (1998) pH-dependent gating in the Streptomyces lividans K+ channel. Biochemistry 37, 3229–3236.

    Article  PubMed  CAS  Google Scholar 

  30. Yellen, G. (1998) The moving parts of voltagegated ion channels. Quarterly Rev. Biophys. 31, 239–295.

    Article  CAS  Google Scholar 

  31. Doyle, D. A., Morais, C. J., Pfuetzner, R. A., Kuo, A., Gulbis, J. M., Cohen, S. L., et al. (1998) The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77.

    Article  PubMed  CAS  Google Scholar 

  32. Jiang, Y., Lee, A., Chen, J., Cadene, M., Chait, B. T., and MacKinnon, R. (2002) The open pore conformation of potassium channels. Nature 417, 523–526.

    Article  PubMed  CAS  Google Scholar 

  33. Bett, G. C. L. and Rasmusson, R. L. Models of cardiac ion channels, in: Quantitative Cardiac Electrophysiology. (Cabo, C. and Rosenbaum, D. S. eds.) Marcel Dekker, Inc., New York, NY, 2002.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY

    Glenma C. L. Bett & Randall L. Rasmusson

Authors
  1. Glenma C. L. Bett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Randall L. Rasmusson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Randall L. Rasmusson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bett, G.C.L., Rasmusson, R.L. Functionally-distinct proton-binding in HERG suggests the presence of two binding sites. Cell Biochem Biophys 39, 183–193 (2003). https://doi.org/10.1385/CBB:39:3:183

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/CBB:39:3:183

Index Entries

Search

Navigation