Enzymes of the cAMP-dependent phosphodiesterase type 4 (PDE4) family are important in hydrolyzing cAMP produced by G-protein coupled receptor (GPCR) stimulated adenylyl cyclases. In brain more than 90% of cAMP formed by the stimulation of GPCRs is hydrolyzed by PDE4 enzymes (1). Members of the PDE4A, B and D family are associated with GPCRs (adrenergic and dopaminergic) signaling (6, 7). In testis PDE4A variants are expressed exclusively in primary and secondary germ cells and are believed to be responsible for normal spermatogenesis (8). PDE4 enzymes are also important molecular targets for variety of therapeutic agents like antidepressants, anti-asthmatics, and anti- inflammatory drugs. PDE4 family comprised of 4 genes (PDE4A, B, C and D), each exhibiting multiple isozymes due to alternate splicing that leads to a larger number of distinct PDE4 variants (2). Rolipram, an antidepressant drug, inhibits all the members of PDE4 family in mM concentration range. In rodents, inhibition of PDE4 enzymes attenuated short- and long-term memory impairment produced by scopolamine and MK801 administration (3). Members of the PDE4 family are regulated/activated by phosphorylation/dephosphorylation by cAMP-dependent protein kinase A and phosphatases (4). Two conserved phosphorylation motifs have been identified in PDE4A subtype variants (i) Phosphorylation at PKA site and (ii) an ERK kinase site. Phosphorylation at PKA site resulted in significant increase I enzymatic activity of PDE4A variants. Phosphorylation state, protein-protein interactions and cellular trafficking of PDE4A enzymes play an important role in cAMP compartmentalization and cAMP- dependent signaling (5).
Alternate names: 2EL, 5'-cyclic phosphodiesterase 4A, DPDE2, PDE4, PDE46, PDE4A1, PDE4A10, PDE4A11, PDE4A4, PDE4A4B, PDE4A6, PDE4A7, PDE4A8, PDE4A8A, Phosphodiesterase 4A, Phosphodiesterase-4A cAMP-specific, RD1, cAMP-specific 3'