| First Author | Rybalkin SD | Year | 2003 |
| Journal | EMBO J | Volume | 22 |
| Issue | 3 | Pages | 469-78 |
| PubMed ID | 12554648 | Mgi Jnum | J:82087 |
| Mgi Id | MGI:2450821 | Doi | 10.1093/emboj/cdg051 |
| Citation | Rybalkin SD, et al. (2003) PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. EMBO J 22(3):469-78 |
| abstractText | 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. |
