Phosphodiesterases: CNS Functions and Diseases

Susana R. Neves-Zaph

A large number of neuromodulators activate G-protein coupled receptors (GPCRs) and mediate their cellular actions via the regulation of intracellular cAMP, the small highly diffusible second messenger. In fact, in the same neuron several different GPCRs can regulate cAMP with seemingly identical timecourses that give rise to distinct signaling outcomes, suggesting that cAMP does not have equivalent access to all its downstream effectors and may exist within defined intracellular pools or domains. cAMP compartmentalization is the process that allows the neuron to differentially interpret these various intracellular cAMP signals into cellular response. The molecular mechanisms that give rise to cAMP compartmentalization are not fully understood, but it is thought that phosphodiesterases (PDEs), the enzymes that degrade cAMP, significantly contribute to this process. PDEs, as the sole mechanism of signal termination for cAMP, hold great promise as therapeutic targets for pathologies that are due to the dysregulation of intracellular cAMP signaling. Due to their diverse catalytic activity, regulation and localization each PDE subtype expressed in a given neuron may have a distinct role on downstream signaling.