doi: 10.1161/01.RES.0000261934.56938.38
© 2007 American Heart Association, Inc.
Reviews |
cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System
A Molecular Toolbox for Generating Compartmentalized cAMP Signaling
From the Molecular Pharmacology Group (M.D.H., G.S.B.), Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, United Kingdom; and Department of Pharmacology and Toxicology (D.H.M.), Queen’s University, Kingston, Ontario, Canada.
Correspondence to Prof Miles Houslay, Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, UK. E-mail M.Houslay{at}bio.gla.ac.uk
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 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 AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysis by cyclic nucleotide phosphodiesterases (PDEs) controlled both the magnitude and the duration of its influence. Recent evidence shows that PDEs also act as coincident detectors linking cyclic-nucleotide– and non–cyclic-nucleotide–based cellular signaling processes and are tethered with great selectively to defined intracellular structures, thereby integrating and spatially restricting their cellular effects in time and space. Although 11 distinct families of PDEs have been defined, and cells invariably express numerous individual PDE enzymes, a large measure of our increased appreciation of the roles of these enzymes in regulating cyclic nucleotide signaling has come from studies on the PDE4 family. Four PDE4 genes encode more than 20 isoforms. Alternative mRNA splicing and the use of different promoters allows cells the possibility of expressing numerous PDE4 enzymes, each with unique amino-terminal-targeting and/or regulatory sequences. Dominant negative and small interfering RNA–mediated knockdown strategies have proven that particular isoforms can uniquely control specific cellular functions. Thus the protein kinase A phosphorylation status of the ß2 adrenoceptor and, thereby, its ability to switch its signaling to extracellular signal-regulated kinase activation, is uniquely regulated by PDE4D5 in cardiomyocytes. We describe how cardiomyocytes and vascular smooth muscle cells selectively vary both the expression and the catalytic activities of PDE4 isoforms to regulate their various functions and how altered regulation of these processes can influence the development, or resolution, of cardiovascular pathologies, such as heart failure, as well as various vasculopathies.
Key Words: phosphodiesterase-4 • cAMP • cardiomyocytes • vascular smooth muscle cells • compartmentation • ß2 adrenoceptor • ß-arrestin
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