Activation of cardiac human ether-a-go-go related gene potassium currents is regulated by alpha(1A)-adrenoceptors.
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, I(Kr). Previous studies have revealed that hERG channel activation is modulated by activation of the beta-adrenergic system. In contrast, the influence of the alpha-adrenergic signal transduction cascade on hERG currents is less well understood. The present study examined the regulation of hERG currents by alpha(1A)-adrenoceptors. hERG channels and human alpha(1A)-adrenoceptors were heterologously coexpressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage clamp technique. Stimulation of alpha(1A)-receptors by applying 20 microM phenylephrine caused hERG current reduction due to a 9.6-mV shift of the activation curve towards more positive potentials. Simultaneous application of the alpha(1)-adrenoceptor antagonist prazosin (20 microM) prevented the activation shift. Inhibition of PKC (3 microM Ro-32-0432) or PKA (2.5 microM KT 5720) abolished the alpha-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/I(Kr) potassium currents are modulated by alpha(1A)-adrenoceptors via PKC and PKA independently of direct channel phosphorylation. This novel regulatory pathway of alpha1-adrenergic hERG current regulation provides a link between stress and ventricular arrhythmias, in particular in patients with heart disease.
Thomas
Dierk
D
Department of Cardiology, Medical University Hospital, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany. Dierk_Thomas@med.uni-heidelberg.de
Wu
Kezhong
K
Wimmer
Anna-Britt
AB
Zitron
Edgar
E
Hammerling
Bettina C
BC
Kathöfer
Sven
S
Lueck
Sonja
S
Bloehs
Ramona
R
Kreye
Volker A W
VA
Kiehn
Johann
J
Katus
Hugo A
HA
Schoels
Wolfgang
W
Karle
Christoph A
CA
D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D014982:Xenopus laevis
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D018340:Receptors, Adrenergic, alpha-1; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D011188:Potassium