cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System

Abstract

Abstract-Cyclic AMP regulates a vast number of distinct events in all cells. Early studies established that its hydrolysisby 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 ␤ 2 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. (Circ Res. 2007;100:950-966.)

In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease

“…PDEs are crucial for negatively regulating cAMP levels and thus for the control of the individual local cAMP signalling events. At least five PDE families (PDE1-4 and 8) are expressed in the heart and can rapidly hydrolyse cAMP to AMP, thereby creating multiple contiguous cAMP microdomains 1,[9][10][11][12] . This enables the specificity of each cAMP response associated with local pools of PKA responsible for phosphorylation of particular downstream effectors.…”

Regulation of amygdalar PKA by β-arrestin-2/phosphodiesterase-4 complex is critical for fear conditioning

“…Houslay and colleges demonstrated that inhibition of PDE-4 affects CNS responses including depression, schizophrenia and memory (22)(23)(24)(25)(26). ␤-arrestin-2 can form stable complex with PDE-4s (27,28), and PDE-4D5 is the preferred binding partner of ␤-arrestin-2 (29).…”

Location, location, location: PDE4D5 function is directed by its unique N-terminal region

“…The mammalian PDE super-family contains 11 groups (PDE1-PDE11) that are classified based upon structural considerations such as protein domains, sequence homology, and enzymatic properties including substrate specificity, activity and sensitivity to endogenous regulators and inhibitors [11]. Reviews on the regulation, function and pharmacology of the different PDE families are many, however the current review will concentrate on one family that are particularly known for intracellular targetting, PDE4 [12]. The PDE4 gene family consist of 4 genes, PDE4A, B, C and D that encode over 20 different PDE4 isoforms due to alternative mRNA splicing.…”