Dynamic control of hERG/I(Kr) by PKA-mediated interactions with 14-3-3.
IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in beta-adrenergic responses. Elevations of cAMP as seen in beta-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3epsilon. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.
Kagan
Anna
A
Department of Medicine (Cardiology), Albert Einstein College of Medicine, Bronx, New York 10461, USA.
McDonald
Thomas V
TV
D048948:14-3-3 Proteins / Q000378:metabolism*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008133:Long QT Syndrome; D010766:Phosphorylation; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*
D048948:14-3-3 Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D024642:Potassium Channels, Voltage-Gated; D017868:Cyclic AMP-Dependent Protein Kinases