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 a-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 muM 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 muM) prevented the activation shift. Inhibition of PKC (3 muM Ro-32-0432) or PKA (2.5 muM KT 5720) abolished the a-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 alpha(1)-adrenergic hERG current regulation provides a link between stress and ventricular arrhythmias, in particular in patients with heart disease.