Intracellular targeting of phosphodiesterase-4 underpins compartmentalized cAMP signaling

The phosphodiesterase-4 (PDE4) enzyme belongs to a family of cAMP-dependent phosphodiesterases that provide the major means of hydrolyzing and, thereby, inactivating the key intracellular second messenger, cAMP. As such, PDE4s are central to the regulation of many diverse signaling processes that allow cells to respond to external stimuli. Four genes (4A, 4B, 4C, and 4D) encode around 20 distinct isoform members of the PDE4 family. Each isoform is characterized by a unique N-terminal region. PDE4s are multidomain metallohydrolases with each domain serving particular roles allowing them to be targeted to varying regions and organelles of intracellular space and regulated in distinct fashions by phosphorylation and protein-protein interaction. Although identical in catalytic function, each isoform locates to distinct regions within the cell so as to create and manage spatially distinct pools of cAMP. The multiplicity of partners associating with members of the four gene PDE4 family places these enzymes in key regulatory positions, permitting them to channel complex biological signals via fundamental signaling cohorts such as G-protein-coupled receptors (GPCRs), arrestins, A-kinase-anchoring proteins (AKAPs), and tyrosyl family kinases. The cAMP cascade has long been linked to cellular growth and embryogenesis and with this comes the implication that PDE4 may play considerable roles in the regulation of progeny development in maturing cells and tissues.