Phosphodiesterases in the Central Nervous System

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Phosphodiesterases (PDEs) represent important cornerstones of cGMP signaling in various tissues. Since the discovery of PDE activity in 1962, it has become clear that the functional characteristics of PDEs and their role in cyclic nucleotide signaling are fairly complex. On the one hand, members of the PDE family responsible for the hydrolysis of cGMP affect cellular responses by shaping cGMP signals derived from the activation of soluble cytosolic and/or membrane bound particulate guanylyl cyclases. Conversely, PDEs may function as downstream effectors in the cGMP signaling cascade. To make things even more sophisticated, cGMP modulates the activity of several PDEs either directly, by binding to a regulatory domain, or indirectly, through phosphorylation, and the result can be either inhibition or stimulation of the enzyme, depending on the subtype. Furthermore, cross-talk between cGMP and cAMP signaling is achieved by cGMP-dependent modulation of PDEs hydrolyzing cAMP and vice versa. Mammals possess at least 21 PDE genes and often express a set of PDEs in a tissue- and differentiation-dependent manner. Given these premises, it is still a challenging task to elucidate the physiological function(s) of individual PDE genes. The present chapter focuses on the role of PDEs as regulators of neuronal functions. Useful information regarding this topic has been gained by studying (1) the expression pattern of PDEs in the CNS, (2) the association of PDEs with specific macromolecular signaling complexes and (3) the phenotypes associated with mutations or ablation of PDE genes in man, mice and fruit flies, respectively. PDEs degrading cGMP and/or being regulated by cGMP have been implicated in cognition and learning, Parkinson's disease, attention deficit hyperactivity disorder, psychosis and depression. Correspondingly, modulators of PDEs have become attractive tools for treatment of these disorders of CNS function.