Chapter 196 - Phosphodiesterase-9A: A cGMP-Specific Enzyme

Abstract

This chapter describes the primary structure, enzymatic characteristics, inhibitor sensitivity, and gene expression of PDE9A, a cGMP-specific PDE with the lowest Km value among all PDEs. Several intracellular small molecules, including cyclic nucleotides (cAMP and cGMP) and ions, act as second messengers to regulate various cellular functions. For instance, cGMP, which is produced by extracellular molecules via activation of guanylyl cyclases, activates cGMP-dependent protein kinases (PKG) and cGMP-gated ion channels. This activation can lead to relaxation of vascular smooth muscle, airway distension, inhibition of cell proliferation, inhibition of platelet aggregation, neuronal transmission, visual signaling, and apoptosis. Cyclic nucleotide phosphodiesterases (PDEs), which comprise 11 families classified on the basis of amino acid sequence homology and substrate specificity, are known to hydrolyze cyclic nucleotides. PDE9A inhibitors improve long-term potentiation in several animal models of cognition. Specific inhibitors of each PDE are used as drugs to treat a variety of diseases. For instance, PDE5 inhibitors, such as sildenafil, vardenafil, tadalafil, and udenafil, are prescribed for erectile dysfunction. On the other hand, cilostazol, a PDE3 inhibitor, is used to treat intermittent claudication. Several PDE4 inhibitors are also being developed for treatment of allergies, including asthma and chronic obstructive pulmonary disease. Thus, PDE families are considered to be drug targets, and many pharmaceutical companies are developing new PDE inhibitors.