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A more recent version of this article appeared on September 1, 2004
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Submitted on December 15, 2003
Revised on June 17, 2004
Accepted on June 28, 2004
Institut für Pharmakologie und Toxikologie, Medizinische Fakultät, Ruhr-Universität Bochum, Bochum, Germany
Monitoring Editor: Guido Guidotti
Most effects of the messenger molecule NO are mediated by cGMP which is formed by NO-sensitive guanylyl cyclase (GC) and degraded by phosphodiesterases (PDE). In platelets, NO elicits a spike-like cGMP response and causes a sustained desensitization. Both characteristics have been attributed to PDE5 activation caused by cGMP-binding to its regulatory GAF domain. Activation is paralleled by phosphorylation whose precise function remains unknown.
Here, we report reconstitution of all features of the NO-induced cGMP response in HEK cells by coexpressing NO-sensitive GC and PDE5. The spike-like cGMP response was blunted when PDE5 phosphorylation was enhanced by additional overexpression of cGMP-dependent protein kinase (PKG). Analysis of PDE5 activation in vitro revealed a discrepancy between the cGMP concentrations required for activation (µM) and reversal of activation (nM) indicating the conversion of a low affinity state to a high affinity state upon binding of cGMP. Phosphorylation even increased the high apparent affinity enabling PDE5 activation to persist at extremely low cGMP concentrations.
Our data suggest that the spike-like shape and the desensitization of the cGMP response are potentially inherent to every GC- and PDE5-expressing cell. Phosphorylation of PDE5 appears to act as memory switch for activation leading to long-term desensitization of the signaling pathway.
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