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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
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Published on: July 3, 2013

Activation of cardiac human ether-a-go-go related gene potassium currents is regulated by alpha(1A)-adrenoceptors

Dierk Thomas1, Kezhong Wu, Anna-Britt Wimmer

  • 1Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. Dierk_Thomas@med.uni-heidelberg.de

Journal of Molecular Medicine (Berlin, Germany)
|September 15, 2004
PubMed

Insights

Alpha-1A adrenoceptors regulate cardiac potassium channels (hERG) via protein kinase pathways, independent of direct phosphorylation. This finding links adrenergic stimulation during stress to ventricular arrhythmias in heart disease patients.

Area of Science:

  • Cardiology
  • Molecular Biology
  • Pharmacology

Background:

  • Patients with heart disease are prone to life-threatening ventricular arrhythmias during stress.
  • Adrenergic stimulation is implicated in regulating cardiac action potential, but alpha-adrenergic effects on hERG channels are unclear.
  • Human ether-a-go-go related gene (hERG) potassium channels are crucial for cardiac repolarization (I(Kr)).

Purpose of the Study:

  • To investigate the regulation of hERG currents by alpha(1A)-adrenoceptors.
  • To elucidate the signaling pathways involved in alpha(1A)-adrenoceptor-mediated modulation of hERG channels.

Main Methods:

  • Heterologous co-expression of hERG channels and human alpha(1A)-adrenoceptors in Xenopus laevis oocytes.
  • Two-microelectrode voltage clamp technique to measure hERG currents.
  • Pharmacological manipulation using phenylephrine, prazosin, and inhibitors of protein kinase C (PKC) and protein kinase A (PKA).

Main Results:

  • Alpha(1A)-adrenoceptor stimulation with phenylephrine reduced hERG current by shifting the activation curve to more positive potentials.
  • Prazosin blocked the phenylephrine-induced shift, confirming alpha(1)-adrenoceptor involvement.
  • Inhibition of PKC and PKA abolished the shift, indicating their requirement in the signaling pathway.
  • The effect persisted even when known phosphorylation sites on hERG were deleted, suggesting indirect regulation.

Conclusions:

  • Cardiac repolarizing hERG/I(Kr) potassium currents are modulated by alpha(1A)-adrenoceptors through PKC and PKA signaling.
  • This modulation occurs independently of direct channel phosphorylation.
  • A novel regulatory pathway linking alpha1-adrenergic signaling to hERG current provides insight into stress-induced ventricular arrhythmias in heart disease.

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