Abstract
Cardiac function is regulated critically by the autonomic nervous system to adapt to the physical activity and emotional stress. A slowly activating cardiac potassium channel ( I Ks) is modulated by stimulation of the sympathetic nervous system (SNS) and contributes to cardiac action potential shortening in the face of concomitant increases in heart rate. Activation of β-adrenergic receptors in response to SNS stimulation results in protein kinase A (PKA)-mediated phosphorylation of I Ks channels. We have found that the functional regulation of the I Ks channel by PKA requires the A kinase-anchoring protein (AKAP) Yotiao. Yotiao forms a macromolecular complex with the channel and recruits key enzymes such as PKA and protein phosphatase 1 (PP1) to control the phosphorylation state of I Ks. Our recent findings revealed a more active role of Yotiao in the PKA modulation of I Ks. We found that Yotiao participates actively in translating the phosphorylation-induced change into altered channel activity. Moreover Yotiao itself can be phosphorylated by PKA upon β-adrenergic stimulation. Ablation of Yotiao phosphorylation impairs PKA-induced changes in I Ks voltage-dependent activation and current kinetics. Taken together we have evidence to suggest that Yotiao plays dual roles in the PKA modulation of the I Ks channel. It acts not only as an adaptor protein to coordinate enzymatic reactions but also as an active regulator that directly affects channel function.
Published Version
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