Phosphodiesterases: CNS Functions and Diseases

Graeme B. Bolger

The PDE4 cyclic nucleotide phosphodiesterases are essential regulators of cAMP abundance in the CNS through their ability to regulate PKA activity, the phosphorylation of CREB, and other important elements of signal transduction. In pre-clinical models and in early-stage clinical trials, PDE4 inhibitors have been shown to have antidepressant and memory-enhancing activity. However, the development of clinically-useful PDE4 inhibitors for CNS disorders has been limited by variable efficacy and significant side effects. Recent structural studies have greatly enhanced our understanding of the molecular configuration of PDE4 enzymes, especially the "long" PDE4 isoforms that are abundant in the CNS. The new structural data provide a rationale for the development of a new generation of PDE4 inhibitors that specifically act on long PDE4 isoforms. These next generation PDE4 inhibitors may also be capable of targeting the interactions of select long forms with their "partner" proteins, such as RACK1, β-arrestin, and DISC1. They would therefore have the ability to affect cAMP levels in specific cellular compartments and target localized cellular functions, such as synaptic plasticity. These new agents might also be able to target PDE4 populations in select regions of the CNS that are implicated in learning and memory, affect, and cognition. Potential therapeutic uses of these agents could include affective disorders, memory enhancement, and neurogenesis.