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PMID:12554648
| Citation |
Rybalkin, SD, Rybalkina, IG, Shimizu-Albergine, M, Tang, XB and Beavo, JA (2003) PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J. 22:469-78 |
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| Abstract |
cGMP-specific, cGMP-binding phosphodiesterase (PDE5) regulates such physiological processes as smooth muscle relaxation and neuronal survival. PDE5 contains two N-terminal domains (GAF A and GAF B), but the functional roles of these domains have not been determined. Here we show that recombinant PDE5 is activated directly upon cGMP binding to the GAF A domain, and this effect does not require PDE5 phosphorylation. PDE5 exhibited time- and concentration-dependent reversible activation in response to cGMP, with the highest activation (9- to 11-fold) observed at low substrate concentrations (0.1 micro M cGMP). A monoclonal antibody directed against GAF A blocked cGMP binding, prevented PDE5 activation and decreased basal activity, revealing that PDE5 in its non-activated state has low intrinsic catalytic activity. Activated PDE5 showed higher sensitivity towards sildenafil than non-activated PDE5. The stimulatory effect of cGMP binding on the catalytic activity of PDE5 suggests that this mechanism of enzyme activation may be common among other GAF domain-containing proteins. The data also suggest that development of agonists and antagonists of PDE5 activity based on binding to this site might be possible. |
| Links |
PubMed PMC140735 Online version:10.1093/emboj/cdg051 |
| Keywords |
3',5'-Cyclic-GMP Phosphodiesterases/chemistry; 3',5'-Cyclic-GMP Phosphodiesterases/genetics; 3',5'-Cyclic-GMP Phosphodiesterases/metabolism; Animals; Antibodies, Monoclonal/metabolism; Cell Line; Cyclic GMP/metabolism; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Activation; Humans; Mice; Mutagenesis, Site-Directed; Phosphodiesterase Inhibitors/metabolism; Phosphorylation; Piperazines/metabolism; Protein Binding; Protein Structure, Tertiary; Purines; Recombinant Proteins/chemistry; Recombinant Proteins/genetics; Recombinant Proteins/metabolism; Sulfones |
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