The cAMP pathway has key physiological effects on heart function and is essential for the chronotropic, inotropic and lusitropic effects during the 'fight-or-flight' response. However, chronic activation of the cAMP pathway induces hypertrophic growth and ventricular dysfunction, which ultimately leads to the development of chamber dilatation and heart failure. Despite the description of a number of alterations in the cAMP pathway during hypertrophy and heart failure, the exact mechanisms accounting for the cardiotoxicity of this pathway are not fully understood. Much research has been dedicated to understanding the roles in heart for types 5 and 6 adenylyl cyclase (AC), the enzymes that synthesize cAMP. However roles for additional ACs expressed in cardiac myocytes have been largely overlooked. We have recently shown that type 9 AC is not only expressed in adult mouse cardiomyocytes, but is the only AC isoform to associate with the Yotiao- IKs complex in both transgenic mouse models and guinea pig heart. Sympathetic responses increase cAMP signaling which increases IKs current and shortening of the action potential duration to allow sufficient diastolic intervals in the face of increased heart rate. Mutations that disrupt interactons between the IKs channel subunit (KCNQ1) and the scaffolding protein Yotiao give rise to Long-QT syndrome. We have provided significant evidence that adenylyl cyclase (AC) is an integral part of signaling scaffolds known as A-kinase anchoring proteins (AKAPs) that coordinate events both upstream and downstream of cAMP production. We hypothesize that AC9 plays a key role in cAMP regulation of cardiac function and IKs regulation via interactions with Yotiao and possibly additional AKAPs.
Specific Aims will 1) examine the enzymatic regulation of AC9 and real-time production of cAMP in cardiac myocytes, 2) identify and characterize AC9 complexes in cardiac myocytes, and 3) examine the functional roles of AC9 in heart.
Lay summary Long-QT syndrome is defined by fast or irregular heart rhythms. These can trigger fainting, seizures, or even sudden death. Genetic mutations in KCNQ1 or its anchoring protein Yotiao, give rise to ~35% of all patients with Long-QT. We have identified type 9 adenylyl cyclase (AC9) as a component of a macromolecular complex containing KCNQ1-Yotiao that regulates cardiac repolarization. A better understanding of mechanisms that regulate AC9 and its interactions with Yotiao, KCNQ1, and other scaffolding proteins will uncover new strategies for therapeutic interventions of Long-QT and possibly additional heart diseases.
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