Abstract
Adenylyl cyclase type 9 (AC9) is found tightly associated with the scaffolding protein Yotiao and the I Ks ion channel in heart. But apart from potential I Ks regulation, physiological roles for AC9 are unknown. Utilizing a gene-trap mouse line that disrupts expression of AC9, we show that loss of AC9 reduces less than 2% of total AC activity in heart but eliminates Yotiao-associated AC activity. AC9 -/- mice exhibit no structural abnormalities but show a significant bradycardia. Global changes in PKA phosphorylation patters are not altered in AC9 -/- heart, however basal phosphorylation of heat shock protein 20 (Hsp20) is significantly decreased. AC9 binds Hsp20 in a Yotiao-independent manner, while deletion of AC9 decreases Hsp20-associated AC activity in heart, consistent with and an AC9-Hsp20 complex. Phosphorylation of Hsp20 occurs largely in ventricles and is vital for the cardioprotective effects of Hsp20. Decreased Hsp20 phosphorylation suggests a potential baseline ventricular defect for AC9 -/- . Doppler echocardiography of AC9 -/- mice displays a decrease in the early ventricular filling velocity and ventricular filling ratio (E/A), indicative of grade 1 diastolic dysfunction. Our findings unveil potential new roles for AC9 in cardiac function and emphasize the importance of local cAMP production in the context of macromolecular complexes.
Published Version
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