Phosphorylation increases affinity of the phosphodiesterase-5 catalytic site for tadalafil

The Journal of Pharmacology and Experimental Therapeutics
Emmanuel P BessayJ D Corbin

Abstract

Phosphodiesterase-5 (PDE5) is phosphorylated at a single serine residue by cyclic nucleotide-dependent protein kinases. To test for a direct effect of phosphorylation on the PDE5 catalytic site, independent of cGMP binding to the allosteric sites of the enzyme, binding of the catalytic site-specific substrate analog [(3)H]tadalafil to PDE5 was measured. Phosphorylation increased [(3)H]tadalafil binding 3-fold, whereas cGMP caused a 1.6-fold increase. Combination of both treatments caused more than 4-fold increase in [(3)H]tadalafil binding, and effects were additive only at submaximal stimulation. Consistent with the increase in affinity, phosphorylation slowed the [(3)H]tadalafil exchange-dissociation rate from PDE5 more than 6-fold. Finally, phosphorylation increased affinity for hydrolysis of a catalytic site-specific cGMP analog, 2'-O-anthraniloyl-cGMP, by approximately 3-fold. The combined results showed that phosphorylation activates PDE5 catalytic site independently of cGMP binding to the allosteric sites. The results suggested that phosphorylation acts in concert with allosteric cGMP binding to stimulate the PDE5 catalytic site, which should promote negative feedback regulation of the cGMP pathway in intact cells. By in...Continue Reading

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Citations

Oct 22, 2010·The Journal of Pharmacology and Experimental Therapeutics·Jens GeduhnRoland Seifert
Aug 19, 2010·Pharmacological Reviews·Sharron H FrancisDavid Sibley
Apr 30, 2011·Physiological Reviews·Sharron H FrancisJackie D Corbin
Aug 21, 2016·American Journal of Physiology. Lung Cellular and Molecular Physiology·Sebastián Castillo-GalánRoberto V Reyes
Dec 22, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Wesam S AhmedKabir H Biswas

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