Abstract 1955 Expression of hERG, a voltage-gated K+ channel alpha-subunit, is affected by combinatorial phosphorylation in the HEK-293 model system

Ventricular cardiomyocyte repolarization is regulated by hERG and KvLQT1, alpha subunits of voltage-gated K+ channels that carry delayed rectifier currents IKr and IKs. Disruption of these currents results in prolonged ventricular action potential durations, which manifest clinically as Long QT syndrome (LQTS). Activation of the sympathetic nervous system via β-adrenergic signaling in LQTS patients can result in arrhythmia, syncope, and sudden cardiac death. Sympathetic stimulation is thought to regulate hERG and KvLQT1 through protein-kinase A (PKA) mediated phosphorylation, but the effects of combinatorial phosphorylation patterns on biogenesis, trafficking, function, and protein-protein interactions remain elusive. Using phosphomutants, we investigated the effects of combinatorial phosphorylation in the four putative PKA-mediated sites in hERG focusing on changes in protein maturation, expression, and cellular localization. Immunoblotting results suggest that different mutant phosphorylation patterns lead to hERG protein under- or overexpression relative to wild-type controls and the phosphonull mutant. Thus, hERG may be phosphorylated at baseline and PKA-mediated phosphorylation could be a mechanism to dynamically regulate hERG expression levels. American Heart Association Institutional Research Enhancement Award (AIREA) 23AIREA1051613 Investigating interactions between the cardiac voltage-gated potassium channel proteins hERG and KvLQT1.