The cyclic monophosphate nucleotides (cyclic adenosine monophosphate [cAMP] and cyclic guanosine monophosphate [cGMP]) are found ubiquitously in mammalian cells and act as second messenger transducers to effect the intracellular actions of a variety of G protein coupled receptors (GPCRs) for hormones, cytokines, and neurotransmitters. Cyclic nucleotides are important intracellular second messengers which play important role in a variety of signal transduction process. The cyclic nucleotides are hydrolyzed and compartmentalized by a family of enzymes called phosphodieterases. One of the many phosphodiesterases that compartmentalized and hydrolyze cGMP in various tissues is phosphodiesterase type 5A (PDE5A). The cGMP is involved in nitric oxide signaling as well as cell signaling associated with natriuretic peptides and gulanylins. Some of the intracellular biding cites for the cGMP include cyclic nucleotide gated ion channels, cGMP dependent protein kinases, and cyclic GMP biding phosphodiesterases (cGB PDEs). The cGB PDEs include PDE2, PDE3, PDE5, PDE5 and PDE10; the members of these families contain various structural and functional motifs that are conserved. Most of these proteins contain dimeric subunits that contain a highly conserved cGMP binding site and a phosphodiesterase catalytic site.