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. (c) 2006 Elsevier GmbH. All rights reserved.