Journal ArticleDOI
Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use
Andrew T. Bender,Joseph A. Beavo +1 more
TLDR
Basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed and how these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered.Abstract:
Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that regulate the cellular levels of the second messengers, cAMP and cGMP, by controlling their rates of degradation. There are 11 different PDE families, with each family typically having several different isoforms and splice variants. These unique PDEs differ in their three-dimensional structure, kinetic properties, modes of regulation, intracellular localization, cellular expression, and inhibitor sensitivities. Current data suggest that individual isozymes modulate distinct regulatory pathways in the cell. These properties therefore offer the opportunity for selectively targeting specific PDEs for treatment of specific disease states. The feasibility of these enzymes as drug targets is exemplified by the commercial and clinical successes of the erectile dysfunction drugs, sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra). PDE inhibitors are also currently available or in development for treatment of a variety of other pathological conditions. In this review the basic biochemical properties, cellular regulation, expression patterns, and physiological functions of the different PDE isoforms will be discussed. How these properties relate to the current and future development of PDE inhibitors as pharmacological agents is especially considered. PDEs hold great promise as drug targets and recent research advances make this an exciting time for the field of PDE research.read more
Citations
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Journal ArticleDOI
Biochemistry and Physiology of Cyclic Nucleotide Phosphodiesterases: Essential Components in Cyclic Nucleotide Signaling
Marco Conti,Joseph A. Beavo +1 more
TL;DR: Some of the major concepts related to the understanding of PDE function and regulation are reviewed including the structure of catalytic and regulatory domains and arrangement in holoenzymes, the nature and function of negative and positive feedback circuits that have been conserved in PDEs from prokaryotes to human, and the emerging association of mutant PDE alleles with inherited diseases.
Journal ArticleDOI
cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action
TL;DR: Current therapies that have successfully targeted the NO-signaling pathway include nitrovasodilators, PDE5 inhibitors, and tadalafil for treatment of a number of vascular diseases including angina pectoris, erectile dysfunction, and pulmonary hypertension, and potential for use of these medications in the treatment of other maladies continues to emerge.
Journal ArticleDOI
Concepts of neural nitric oxide‐mediated transmission
TL;DR: Viewed from a mechanistic perspective, NO conforms to many of the rules governing more conventional neurotransmission, particularly of the metabotropic type, but stands out as being more economical and versatile, attributes that presumably account for its spectacular evolutionary success.
Journal ArticleDOI
Overview of PDEs and Their Regulation
Kenji Omori,Jun Kotera +1 more
TL;DR: Multiple PDEs function as a particular modulator of each cardiovascular function and regulate physiological homeostasis.
Journal ArticleDOI
Advances in targeting cyclic nucleotide phosphodiesterases
Donald H. Maurice,Hengming Ke,Faiyaz Ahmad,Yousheng Wang,Jay Young Chung,Vincent C. Manganiello +5 more
TL;DR: Pharmaceutical interest in PDEs has been reignited by the increasing understanding of the roles of individual P DEs in regulating the subcellular compartmentalization of specific cyclic nucleotide signalling pathways, by the structure-based design of novel specific inhibitors and by the development of more sophisticated strategies to target individual PDE variants.
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TL;DR: Sildenafil is shown to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection.
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AKAP signalling complexes: focal points in space and time
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