PDE5 activation by cGMP does not require, but is enhanced by, phosphorylation (open circles).

Ashort burst of nitric oxide (NO) is remembered by a phosphodiesterase long after NO levels decline, according to results on page 719 by Mullershausen et al. The memory of this enzyme, PDE5, may be responsible for the tolerance that patients develop to nitrovasodilators like nitroglycerin.

Nitrovasodilators are NO- releasing compounds that are used to treat coronary heart disease. NO increases cellular cGMP levels, which lowers blood pressure by both relaxing blood vessels and inhibiting platelet aggregation. But platelets rapidly decrease NO-induced cGMP and thus become desensitized to later NO exposure. Circumstantial evidence suggests that the cGMP is degraded upon phosphorylation of the phosphodiesterase PDE5 by a cGMP-dependent kinase. The new article describes a more direct route of cGMP self-limitation.

As expected, NO-induced PDE5 phosphorylation required cGMP increases and the cGMP-dependent kinase cGKI. Yet phosphorylation was not necessary for PDE5 activation by cGMP, as shown using cGKI-deficient mice. Instead, cGMP was sufficient to activate PDE5. Others recently showed that cGMP binds to and activates PDE5. This interaction probably provides the direct mechanism for NO-induced PDE5 activation. Low concentrations of cGMP, however, stimulated only phosphorylated PDE5, suggesting that the modification may increase cGMP affinity.

A small, transient NO stimulus dampened subsequent cGMP production in response to NO ≤1 h later, at which time PDE5 was still active. Inhibition of this active PDE5 may be necessary to achieve lasting nitrovasodilator therapy. ▪