Abstract
Cyclic AMP (cAMP) is a key second messenger in all cells. It is compartmentalized within cells and its levels are controlled, as a result of spatially discrete signaling cassettes controlling its generation, detection and degradation. Underpinning compartmentalized cAMP signaling are approximately 20 members of the phosphodiesterase-4 (PDE4) family. The selective inhibition of this family generates profound, functional effects and PDE4 inhibitors are currently under development to provide potential, novel therapeutics for the treatment of inflammatory diseases, such as asthma, chronic obstructive pulmonary disease and psoriasis, as well as treating depression and serving as cognitive enhancers. Here, we delineate the range of PDE4 isoforms, their role in signaling, their structural biology and related preclinical and clinical pharmacology.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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3',5'-Cyclic-AMP Phosphodiesterases / chemistry*
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3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
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Alzheimer Disease / drug therapy
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Alzheimer Disease / enzymology
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Asthma / drug therapy
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Asthma / enzymology
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Catalytic Domain
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Cyclic AMP / physiology
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Cyclic Nucleotide Phosphodiesterases, Type 4
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Depression / drug therapy
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Depression / enzymology
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Drug Design
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Humans
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / chemistry
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Isoenzymes / metabolism
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Leukocytes / drug effects
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Leukocytes / enzymology
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Lung Diseases, Obstructive / drug therapy
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Lung Diseases, Obstructive / physiopathology
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Parkinson Disease / drug therapy
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Parkinson Disease / enzymology
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Phosphodiesterase Inhibitors / chemistry
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Phosphodiesterase Inhibitors / pharmacology*
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Protein Conformation
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Signal Transduction
Substances
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Antineoplastic Agents
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Isoenzymes
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Phosphodiesterase Inhibitors
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Cyclic AMP
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3',5'-Cyclic-AMP Phosphodiesterases
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Cyclic Nucleotide Phosphodiesterases, Type 4