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(Circulation Research. 2007;100:1569.)
© 2007 American Heart Association, Inc.

Reviews

cAMP and cGMP Signaling Cross-Talk

Role of Phosphodiesterases and Implications for Cardiac Pathophysiology

Manuela Zaccolo, Matthew A. Movsesian

From the Dulbecco Telethon Institute at the Venetian Institute of Molecular Medicine (M.Z.), Padova, Italy; and the Cardiology Section, Veterans Affairs Salt Lake City Health Care System (M.A.M.), and Departments of Internal Medicine (Cardiology) and Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah.

Correspondence to Dr Manuela Zaccolo, Venetian Institute for Molecular Medicine, Room G210, Via Orus 2, Padova 35129, Italy. E-mail manuela.zaccolo{at}unipd.it

This Review is part of a thematic series on Phosphodiesterases, which includes the following articles:

Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases

Overview of PDEs and their Regulation

Regulation of Phosphodiesterase 3 (PDE3) and Inducible cAMP Early Repressor in the Heart

cAMP Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling

cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology

PDE5 and Regulation of Vessel and Heart Function
David A. Kass Editor

Cyclic nucleotide phosphodiesterases regulate cAMP-mediated signaling by controlling intracellular cAMP content. The cAMP-hydrolyzing activity of several families of cyclic nucleotide phosphodiesterases found in human heart is regulated by cGMP. In the case of PDE2, this regulation primarily involves the allosteric stimulation of cAMP hydrolysis by cGMP. For PDE3, cGMP acts as a competitive inhibitor of cAMP hydrolysis. Several cGMP-mediated responses in cardiac cells, including a potentiation of Ca²⁺ currents and a diminution of the responsiveness to ß-adrenergic receptor agonists, have been shown to result from the effects of cGMP on cAMP hydrolysis. These effects appear to be dependent on the specific spatial distribution of the cGMP-generating and cAMP-hydrolyzing proteins, as well as on the intracellular concentrations of the two cyclic nucleotides. Gaining a more precise understanding of how these cross-talk mechanisms are individually regulated and coordinated is an important direction for future research.

Key Words: phosphodiesterases • signaling cross-talk • cAMP • cGMP • compartmentalization

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