Dual roles of the A kinase-anchoring protein Yotiao in the modulation of a cardiac potassium channel: A passive adaptor versus an active regulator

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 (IKs) 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 IKs channels. We have found that the functional regulation of the IKs 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 IKs. Our recent findings revealed a more active role of Yotiao in the PKA modulation of IKs. 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 IKs voltage-dependent activation and current kinetics. Taken together we have evidence to suggest that Yotiao plays dual roles in the PKA modulation of the IKs channel. It acts not only as an adaptor protein to coordinate enzymatic reactions but also as an active regulator that directly affects channel function.