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Description
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Enzymes of the cAMP-dependent phosphodiesterase type 4 (PDE4) family are important inhydrolyzing cAMP produced by G-protein coupled receptor (GPCR) stimulated adenylylcyclases. In brain more than 90% of cAMP formed by the stimulation of GPCRs ishydrolyzed by PDE4 enzymes (1). Members of the PDE4A, B and D family are associatedwith GPCRs (adrenergic and dopaminergic) signaling (6, 7). ERK mitogen activated protein kinase and cAMP pathways are important regulators forcross talk between. In testis PDE4A variants are expressed exclusively in primary andsecondary germ cells and are believed to be responsible for normal spermatogenesis (8). PDE4 enzymes are also important molecular targets for variety of therapeutic agents likeantidepressants, anti-asthmatics, and anti-inflammatory drugs. PDE4 family comprised of4 genes (PDE4A, B, C and D), each exhibiting multiple isozymes due to alternate splicingthat leads to a larger number of distinct PDE4 variants (2). Rolipram, an antidepressantdrug, inhibits all the members of PDE4 family in mM concentration range. In rodents,inhibition of PDE4 enzymes attenuated short- and long-term memory impairment producedby scopolamine and MK801 administration (3). Members of the PDE4 family areregulated/activated by phosphorylation/dephosphorylation by cAMP-dependent proteinkinase A and phosphatases (4). Two conserved phosphorylation motifs have beenidentified in PDE4B, C and D, the PDE4A has a single phosphorylation site (i)Phosphorylation at PKA site and (ii) an ERK kinase site. Phosphorylation at PKA siteresulted in significant increase in enzymatic activity of PDE4D variants. Phosphorylationstate, protein-protein interactions and cellular trafficking of PDE4D enzymes play animportant role in cAMP compartmentalization and cAMP-dependent signaling (5).
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