Phosphodiesterases: CNS Functions and Diseases

Lawrence P. Wennogle, Helen Hoxie, Youyi Peng, Joseph P. Hendrick

The focus of this chapter is on the cyclic nucleotide phosphodiesterase 1 (PDE1) family. PDE1 is one member of the 11 PDE families (PDE 1-11). It is the only phosphodiesterase family that is calcium/calmodulin activated. As a result, whereas other families of PDEs 2-11 play a dominant role controlling basal levels of cyclic nucleotides, PDE1 is involved when intra-cellular calcium levels are elevated and, thus, has an "on demand" or activity-dependent involvement in the control of cyclic nucleotides in excitatory cells including neurons, cardiomyocytes and smooth muscle. As a Class 1 phosphodiesterase, PDE1 hydrolyzes the 3' bond of 3'-5'-cyclic nucleotides, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Here, we review evidence for this family of enzymes as drug targets for development of therapies aimed to address disorders of the central nervous system (CNS) and of degenerative diseases. The chapter includes sections on the potential for cognitive enhancement in mental disorders, as well as a review of PDE1 enzyme structure, enzymology, tissue distribution, genomics, inhibitors, pharmacology, clinical trials, and therapeutic indications. Information is taken from public databases. A number of excellent reviews of the phosphodiesterase family have been written as well as reviews of the PDE1 family. References cited here are not comprehensive, rather pointing to major reviews and key publications.