Keynote review: phosphodiesterase-4 as a therapeutic target.
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.
Houslay
Miles D
MD
Division of Biochemistry and Molecular Biology, IBLS, Wolfson Link Building, University of Glasgow, University Avenue, Glasgow, G12 8QQ, Scotland, UK. m.houslay@bio.gla.ac.uk
Schafer
Peter
P
Zhang
Kam Y J
KY
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000737:chemistry* / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology; D020134:Catalytic Domain; D000242:Cyclic AMP / Q000502:physiology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D003863:Depression / Q000188:drug therapy / Q000201:enzymology; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology; D008173:Lung Diseases, Obstructive / Q000188:drug therapy / Q000503:physiopathology; D010300:Parkinson Disease / Q000188:drug therapy / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D015398:Signal Transduction
D000970:Antineoplastic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4