Clinical and molecular genetics of the phosphodiesterases (pdes)

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) are enzymes that have the unique function of terminating cyclic nucleotide signaling by catalyzing the hydrolysis ofcAMPandGMP.They are critical regulators of the intracellular concentrations of cAMP and cGMP as well as of their signaling pathways and downstream biological effects. PDEs have been exploited pharmacologically for more than half a century, and some of the most successful drugs worldwide today affect PDE function.Recently,mutationsinPDEgeneshavebeenidentifiedascausativeofcertainhumangeneticdiseases;evenmore recently, functional variants ofPDEgeneshavebeensuggested to playapotential role in predisposition totumorsand/or cancer,especially incAMP-sensitivetissues.Mousemodelshavebeendevelopedthatpointtowidedevelopmentaleffects of PDEs from heart function to reproduction, to tumors, and beyond. This review brings together knowledge from a variety of disciplines (biochemistry and pharmacology, oncology, endocrinology, and reproductive sciences) with emphasis on recent research on PDEs, how PDEs affect cAMP and cGMP signaling in health and disease, and what pharmacological exploitations of PDEs may be useful in modulating cyclic nucleotide signaling in a way that prevents or treats certain human diseases. © 2014 by the Endocrine Society.