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