Circulation Research. 2005
Published online before print December 15, 2005, doi: 10.1161/01.RES.0000200178.34179.93
Published online before print December 15, 2005, doi: 10.1161/01.RES.0000200178.34179.93
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Submitted on November 30, 2004
Revised on November 22, 2005
Accepted on December 1, 2005
Compartmentalized Phosphodiesterase-2 Activity Blunts 
-Adrenergic Cardiac Inotropy via an NO/cGMP-Dependent Pathway
Marco Mongillo ;
From the Dulbecco Telethon Institute (M.M., A.T., V.L., M.Z.) and Venetian Institute of Molecular Medicine (M.M., A.T., V.L., T.P., M.Z.), Padova, Italy; Department of Cardiology (C.G.T., D.A.K., N.P.), Johns Hopkins Medical Institutions, Baltimore, Md; Division of Biochemistry and Molecular Biology (Y.-F.C., M.D.H.), Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, United Kingdom; Department of Pharmacology (W.R.D.), University of Vermont, Burlington; and Department of Biomedical Sciences (T.P.), University of Padova, Italy.
* To whom correspondence should be addressed. E-mail: manuela.zaccolo{at}unipd.it.
-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP]i in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving 3-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by -adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the -adrenergic pathway. In this, activation of 3-adrenergic receptors counteracts cAMP generation obtained via stimulation of 1/2-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.
Key words: PDE2 • cAMP • cardiomyocytes • fluorescence resonance energy transfer • compartmentalization
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