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Activation of cardiac human ether-a-go-go related gene potassium currents is regulated by α1A-adrenoceptors

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Abstract

Patients with cardiac disease typically develop life-threatening ventricular arrhythmias during physical or emotional stress, suggesting a link between adrenergic stimulation and regulation of the cardiac action potential. Human ether-a-go-go related gene (hERG) potassium channels conduct the rapid component of the repolarizing delayed rectifier potassium current, IKr. Previous studies have revealed that hERG channel activation is modulated by activation of the β-adrenergic system. In contrast, the influence of the α-adrenergic signal transduction cascade on hERG currents is less well understood. The present study examined the regulation of hERG currents by α1A-adrenoceptors. hERG channels and human α1A-adrenoceptors were heterologously coexpressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. Stimulation of α1A-receptors by applying 20 µM phenylephrine caused hERG current reduction due to a 9.6-mV shift of the activation curve towards more positive potentials. Simultaneous application of the α1-adrenoceptor antagonist prazosin (20 µM) prevented the activation shift. Inhibition of PKC (3 µM Ro-32-0432) or PKA (2.5 µM KT 5720) abolished the α-adrenergic activation shift, suggesting that PKC and PKA are required within the regulatory mechanism. The effect was still present when the PKA- and PKC-dependent phosphorylation sites in hERG were deleted by mutagenesis. In summary, cardiac repolarizing hERG/IKr potassium currents are modulated by α1A-adrenoceptors via PKC and PKA independently of direct channel phosphorylation. This novel regulatory pathway of α1-adrenergic hERG current regulation provides a link between stress and ventricular arrhythmias, in particular in patients with heart disease.

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Abbreviations

hERG :

Human ether-a-go-go related gene

PKA :

Protein kinase A

PKC :

Protein kinase C

PMA :

Phorbol 12-myristate-13-acetate

WT :

Wild type

References

  1. Carmeliet E (1993) Mechanisms and control of repolarization. Eur Heart J 14 [Suppl H]:3–13

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Napolitano C, Priori S, Schwartz P (1994) Torsade de pointes. Mechanisms and management. Drugs 47:51–65

    CAS  PubMed  Google Scholar 

  5. Thomas D, Gut B, Wendt-Nordahl G, Kiehn J (2002) The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels. J Pharmacol Exp Ther 300:543–548

    Article  CAS  PubMed  Google Scholar 

  6. Thomas D, Kiehn J, Katus HA, Karle CA (2003) Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res 60:239–245

    Article  Google Scholar 

  7. Sanguinetti MC, Curran ME, Spector PS, Keating MT (1996) Spectrum of HERG K+-channel dysfunction in an inherited cardiac arrhythmia. Proc Natl Acad Sci U S A 93:2208–2212

    Article  CAS  PubMed  Google Scholar 

  8. Viskin S (1999) Long QT syndromes and torsade de pointes. Lancet 354:1625–1633

    Article  CAS  PubMed  Google Scholar 

  9. Lown B (1987) Sudden cardiac death: biobehavioral perspective. Circulation 76:I186–I196

    CAS  PubMed  Google Scholar 

  10. Kamarck T, Jennings JR (1991) Biobehavioral factors in sudden cardiac death. Psychol Bull 109:42–75

    Article  CAS  PubMed  Google Scholar 

  11. Priori S, Napolitano C, Paganini V, Cantu F, Schwartz PJ (1997) Molecular biology of the long QT syndrome: impact on management Pacing Clin Electrophysiol 20:2052–2057

  12. Thomas D, Zhang W, Karle CA, Kathöfer S, Schöls W, Kübler W, Kiehn J (1999) Deletion of protein kinase A phosphorylation sites in the HERG potassium channel inhibits activation shift by protein kinase A. J Biol Chem 274:27457–27462

    Article  CAS  PubMed  Google Scholar 

  13. Cui J, Melman Y, Palma E, Fishman GI, McDonald TV (2000) Cyclic AMP regulates the HERG K(+) channel by dual pathways. Curr Biol 10:671–674

    Article  CAS  PubMed  Google Scholar 

  14. Cui J, Kagan A, Qin D, Mathew J, Melman YF, McDonald TV (2001) Analysis of the cyclic nucleotide binding domain of the HERG potassium channel and interactions with KCNE2. J Biol Chem 276:17244–17251

    Article  CAS  PubMed  Google Scholar 

  15. Kiehn J (2000) Regulation of the cardiac repolarizing HERG potassium channel by protein kinase A. Trends Cardiovasc Med 10:205–209

    Article  CAS  PubMed  Google Scholar 

  16. Kagan A, Melman YF, Krumerman A, McDonald TV (2002) 14–3–3 Amplifies and prolongs adrenergic stimulation of HERG K+ channel activity. EMBO J 21:1889–1898

    Article  CAS  PubMed  Google Scholar 

  17. Karle CA, Zitron E, Zhang W, Kathöfer S, Schoels W, Kiehn J (2002) Rapid component I (Kr) of the guinea-pig cardiac delayed rectifier K (+) current is inhibited by beta(1)-adrenoreceptor activation, via cAMP/protein kinase A-dependent pathways. Cardiovasc Res 53:355–362

    Article  CAS  PubMed  Google Scholar 

  18. Kiehn J, Karle C, Thomas D, Yao X, Brachmann J, Kübler W (1998) HERG potassium channel activation is shifted by phorbol esters via protein kinase A-dependent pathways. J Biol Chem 273:25285–25291

    Article  CAS  PubMed  Google Scholar 

  19. Thomas D, Zhang W, Wu K, Wimmer AB, Gut B, Wendt-Nordahl G, Kathöfer S, Kreye VAW, Katus HA, Schoels W, Kiehn J, Karle CA (2003) Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein. Cardiovasc Res 59:14–26

    Article  CAS  PubMed  Google Scholar 

  20. Barros F, Gomez-Varela D, Vigoria CG, Palomero T, Giraldez T, de la Pena P (1998) Modulation of human erg K+ channel gating by activation of a G protein-coupled receptor and protein kinase C. J Physiol (Lond) 511:333–346

    Google Scholar 

  21. Jiang M, Dun W, Fan JS, Tseng GN (1999) Use-dependent ‘agonist’ effect of azimilide on the HERG channel. J Pharmacol Exp Ther 291:1324–1336

    CAS  PubMed  Google Scholar 

  22. Bian J, Cui J, McDonald TV (2001) HERG K (+) channel activity is regulated by changes in phosphatidyl inositol 4:5-bisphosphate. Circ Res 89:1168–1176

    CAS  PubMed  Google Scholar 

  23. Michelotti GA, Price DT, Schwinn DA (2000) Alpha 1-adrenergic receptor regulation: basic science and clinical implications. Pharmacol Ther 88:281–309

    Article  CAS  PubMed  Google Scholar 

  24. Hirasawa A, Horie K, Tanaka T, Takagaki K, Murai M, Yano J, Tsujimoto G (1993) Cloning, functional expression and tissue distribution of human cDNA for the alpha 1C-adrenergic receptor. Biochem Biophys Res Commun 195:902–909

    Article  CAS  PubMed  Google Scholar 

  25. Kiehn J, Thomas D, Karle CA, Schöls W, Kübler W (1999) Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels. Naunyn-Schmiedebergs Arch Pharmacol 359:212–219

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Wilkinson SE, Parker PJ, Nixon JS (1993) Isoenzyme specificity of bisindolylmaleimides, selective inhibitors of protein kinase C. Biochem J 294:335–337

    CAS  PubMed  Google Scholar 

  28. Kase H, Iwahashi K, Nakanishi S, Matsuda Y, Yamada K, Takahashi M, Murakata C, Sato A, Kaneko M (1987) K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem Biophys Res Commun 142:436–440

    CAS  PubMed  Google Scholar 

  29. Thomas D, Hammerling BC, Wu K, Wimmer AB, Ficker EK, Kirsch GE, Kochan MC, Wible BA, Scholz EP, Zitron E, Kathöfer S, Kreye VAW, Katus HA, Schoels W, Karle CA, Kiehn J (2004) Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action. Br J Pharmacol 142:485–494

    Article  CAS  PubMed  Google Scholar 

  30. Lo CF, Numann R (1998) Independent and exclusive modulation of cardiac delayed rectifying K+ current by protein kinase C and protein kinase A. Circ Res 83:995–1002

    CAS  PubMed  Google Scholar 

  31. Williams CP, Hu N, Shen W, Mashburn AB, Murray KT (2002) Modulation of the human Kv1.5 channel by protein kinase C activation: role of the Kvbeta1.2 subunit. J Pharmacol Exp Ther 302:545–550

    Article  CAS  PubMed  Google Scholar 

  32. McDonald TV, Yu Z, Ming Z, Palma E, Meyers MB, Wang KW, Goldstein SA, Fishman GI (1997) A minK-HERG complex regulates the cardiac potassium current I (Kr). Nature 388:289–292

    Article  CAS  PubMed  Google Scholar 

  33. Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (1999) MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Cell 97:175–187

    Article  CAS  PubMed  Google Scholar 

  34. Kurz T, Yamada KA, DaTorre SD, Corr PB (1991) Alpha 1-adrenergic system and arrhythmias in ischaemic heart disease. Eur Heart J 12 [Suppl F]:88–98

  35. Dabrowska B, Pruszczyk P, Dabrowski A, Feltynowski T, Wocial B, Januszewicz W (1995) Influence of alpha-adrenergic blockade on ventricular arrhythmias, QTc interval and heart rate variability in pheochromocytoma. J Hum Hypertens 9:925–929

    CAS  PubMed  Google Scholar 

  36. Thomas D, Kiehn J, Katus HA, Karle CA (2004) Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, IKr, and the underlying hERG ion channel. Basic Res Cardiol 99:279–287

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (project KI 663/1-1 to J.K.; project KA 1714/1-1 to C.A.K.), from the Deutsche Stiftung für Herzforschung (to D.T.), from the University of Heidelberg (Young Investigator Award and Hans Dengler Research Scholarship to D.T.), from the Novartis Foundation (to D.T.), from the Foundation Cardiology 2000 (Forssman Scholarship to D.T.), and from the German Cardiac Society (Max Schaldach Research Scholarship to D.T.).

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Thomas, D., Wu, K., Wimmer, AB. et al. Activation of cardiac human ether-a-go-go related gene potassium currents is regulated by α1A-adrenoceptors. J Mol Med 82, 826–837 (2004). https://doi.org/10.1007/s00109-004-0582-8

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  • DOI: https://doi.org/10.1007/s00109-004-0582-8

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