Autonomic system stimulation during stress may alter cardiac action potential and therefore induce ventricular arrhythmias.HERG/IKr K+ channels are responsible for controlling action potential duration.We found in the present study that prolonged stimulation of α1A-adrenergic receptor with phenylephrine (PE) increased HERG protein abundance and current density in HEK293 which stably expressed HERG K+ channels and αlA-adrenergic receptors.The action of PE on protein expression was mimicked by a PKC activator, phorbol 12-myristate 13-acetate (PMA), but blocked by a PKC inhibitor, chelerythrine.PE had no effect on protein abundance of Hsp90, Hsp70 and Hsc70.The action of PE was abolished by two proteosome inhibitors, N-acetyl-L-leucyl-L-leucyl-L-norleucinal and MG132, but not by protein synthesis inhibitors, cycloheximide or anisomycin, a specific heat shock protein (Hsp) 90 inhibitor, geldanamycin, or lysosome protease inhibitors, NH4Cl, bafilomycin and lysosome protease inhibitor cocktails.These data suggest that sustained activation of α1A-adrenergic receptor may inhibit HERG protein degradation via proteosome pathway.PE had no effect on either other ion channels such as KvLQT1, Kir2.1, Kv1.4 and Kv3.4 with the same CMV promoter, or PKC phosphorylation site mutant HERG channels, suggesting that the action of PE is specific to HERG and PKC-dependent phosphorylation was responsible for the PE-induced HERG augmentation.Therefore, we demonstrated for the first time that sustained autonomic regulation of cardiac HERG function is via a novel PKC-dependent phosphorylation mechanism.