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 (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 beta-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 beta-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.