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Review Article |
Department of Pharmacology, University of Washington, Seattle, Washington
Abstract
Abstract I. Introduction A. Definition of Phosphodiesterase Enzymes B. Early Studies C. Current Studies—Functional Pools of Cyclic Nucleotides Subserved by Specific Phosphodiesterases D. Why Phosphodiesterases Make Good Drug Targets E. Multiple Forms of Phosphodiesterases—Current Understanding F. Nomenclature G. Crystal Structures 1. Catalytic Domain Structures. 2. Glutamine Switch. 3. Regulatory Domain Structure. 4. Inhibitor Specificity. II. Phosphodiesterase Families A. Phosphodiesterase 1 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. B. Phosphodiesterase 2 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. C. Phosphodiesterase 3 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. D. Phosphodiesterase 4 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Regulation by Phosphorylation. 6. Pharmacology/Function. E. Phosphodiesterase 5 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. F. Phosphodiesterase 6 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. G. Phosphodiesterase 7 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. H. Phosphodiesterase 8 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. I. Phosphodiesterase 9 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. J. Phosphodiesterase 10 Family 1. Overview. 2. Biochemistry/Structure. 3. Localization. 4. Pharmacology/Function. K. Phosphodiesterase 11 Family 1. Overview. 2. Biochemistry/Structure. 3. Genetics/Splicing. 4. Localization. 5. Pharmacology/Function. III. Concluding Remarks: The Future of ''Phosphodiesterase Pharmacology''?
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.
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