PDE4A explained

cAMP-specific 3',5'-cyclic phosphodiesterase 4A is an enzyme that in humans is encoded by the PDE4A gene.^{[1] [2]}

Function

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase (PDE) family, and PDE4 subfamily. This PDE hydrolyzes the secondary messenger, cAMP, which is a regulator and mediator of a number of cellular responses to extracellular signals. Thus, by regulating the cellular concentration of cAMP, this protein plays a key role in many important physiological processes.^[2] Recently, it has been shown through the use of PDE4A knock out mice that PDE4A may play a role in the regulation of anxiety and emotional memory.^[3]

Clinical significance

PDE4A inhibition is a target of a number of drugs including:^{[4] [5] [6]}

• rolipram (antidepressant and antiinflammatory) and cilomilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, 6, and 7
• roflumilast (antiinflammatory) – inhibits PDE4A isoforms 1, 2, and 6
• tofisopam (anxiolytic with alleged antiinflammatory properties) – inhibits PDE4A isoform 1, PDE-10A1, PDE-3, and PDE-2A3

References

Further reading

• Houslay MD, Schafer P, Zhang KY . Keynote review: phosphodiesterase-4 as a therapeutic target . Drug Discovery Today . 10 . 22 . 1503–19 . Nov 2005 . 16257373 . 10.1016/S1359-6446(05)03622-6 .
• Zhang KY, Ibrahim PN, Gillette S, Bollag G . Phosphodiesterase-4 as a potential drug target . Expert Opinion on Therapeutic Targets . 9 . 6 . 1283–305 . Dec 2005 . 16300476 . 10.1517/14728222.9.6.1283 . 46276184 .
• Livi GP, Kmetz P, McHale MM, Cieslinski LB, Sathe GM, Taylor DP, Davis RL, Torphy TJ, Balcarek JM . Cloning and expression of cDNA for a human low-Km, rolipram-sensitive cyclic AMP phosphodiesterase . Molecular and Cellular Biology . 10 . 6 . 2678–86 . Jun 1990 . 2160582 . 360627 . 10.1128/MCB.10.6.2678 .
• Horton YM, Sullivan M, Houslay MD . Molecular cloning of a novel splice variant of human type IVA (PDE-IVA) cyclic AMP phosphodiesterase and localization of the gene to the p13.2-q12 region of human chromosome 19 [corrected] ]. The Biochemical Journal . 308 . 2 . 683–91 . Jun 1995 . 7772058 . 1136980 . 10.1042/bj3080683.
• Sullivan M, Egerton M, Shakur Y, Marquardsen A, Houslay MD . Molecular cloning and expression, in both COS-1 cells and S. cerevisiae, of a human cytosolic type-IVA, cyclic AMP specific phosphodiesterase (hPDE-IVA-h6.1) . Cellular Signalling . 6 . 7 . 793–812 . Sep 1994 . 7888306 . 10.1016/0898-6568(94)00039-5 .
• Bolger G, Michaeli T, Martins T, St John T, Steiner B, Rodgers L, Riggs M, Wigler M, Ferguson K . A family of human phosphodiesterases homologous to the dunce learning and memory gene product of Drosophila melanogaster are potential targets for antidepressant drugs . Molecular and Cellular Biology . 13 . 10 . 6558–71 . Oct 1993 . 8413254 . 364715 . 10.1128/mcb.13.10.6558.
• Huston E, Pooley L, Julien P, Scotland G, McPhee I, Sullivan M, Bolger G, Houslay MD . The human cyclic AMP-specific phosphodiesterase PDE-46 (HSPDE4A4B) expressed in transfected COS7 cells occurs as both particulate and cytosolic species that exhibit distinct kinetics of inhibition by the antidepressant rolipram . The Journal of Biological Chemistry . 271 . 49 . 31334–44 . Dec 1996 . 8940140 . 10.1074/jbc.271.49.31334 . 25157712 . free .
• Sullivan M, Rena G, Begg F, Gordon L, Olsen AS, Houslay MD . Identification and characterization of the human homologue of the short PDE4A cAMP-specific phosphodiesterase RD1 (PDE4A1) by analysis of the human HSPDE4A gene locus located at chromosome 19p13.2 . The Biochemical Journal . 333 . 3 . 693–703 . Aug 1998 . 9677330 . 1219634 . 10.1042/bj3330693.
• McPhee I, Yarwood SJ, Scotland G, Huston E, Beard MB, Ross AH, Houslay ES, Houslay MD . Association with the SRC family tyrosyl kinase LYN triggers a conformational change in the catalytic region of human cAMP-specific phosphodiesterase HSPDE4A4B. Consequences for rolipram inhibition . The Journal of Biological Chemistry . 274 . 17 . 11796–810 . Apr 1999 . 10206997 . 10.1074/jbc.274.17.11796 . 42776400 . free .
• Zhou L, Thompson WJ, Potter DE . Multiple cyclic nucleotide phosphodiesterases in human trabecular meshwork cells . Investigative Ophthalmology & Visual Science . 40 . 8 . 1745–52 . Jul 1999 . 10393044 .
• Secchiero P, Zella D, Curreli S, Mirandola P, Capitani S, Gallo RC, Zauli G . Pivotal role of cyclic nucleoside phosphodiesterase 4 in Tat-mediated CD4+ T cell hyperactivation and HIV type 1 replication . Proceedings of the National Academy of Sciences of the United States of America . 97 . 26 . 14620–5 . Dec 2000 . 11114167 . 18968 . 10.1073/pnas.011512398 . free .
• Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S . HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway . FASEB Journal . 15 . 2 . 483–91 . Feb 2001 . 11156964 . 10.1096/fj.00-0354com . free . 26315564 .
• Lario PI, Bobechko B, Bateman K, Kelly J, Vrielink A, Huang Z . Purification and characterization of the human PDE4A catalytic domain (PDE4A330-723) expressed in Sf9 cells . Archives of Biochemistry and Biophysics . 394 . 1 . 54–60 . Oct 2001 . 11566027 . 10.1006/abbi.2001.2513 .
• Moon E, Lee R, Near R, Weintraub L, Wolda S, Lerner A . Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia . Clinical Cancer Research . 8 . 2 . 589–95 . Feb 2002 . 11839681 .
• Laliberté F, Liu S, Gorseth E, Bobechko B, Bartlett A, Lario P, Gresser MJ, Huang Z . In vitro PKA phosphorylation-mediated human PDE4A4 activation . FEBS Letters . 512 . 1–3 . 205–8 . Feb 2002 . 11852080 . 10.1016/S0014-5793(02)02259-7 . 27637592 . free .
• Baillie GS, Huston E, Scotland G, Hodgkin M, Gall I, Peden AH, MacKenzie C, Houslay ES, Currie R, Pettitt TR, Walmsley AR, Wakelam MJ, Warwicker J, Houslay MD . TAPAS-1, a novel microdomain within the unique N-terminal region of the PDE4A1 cAMP-specific phosphodiesterase that allows rapid, Ca2+-triggered membrane association with selectivity for interaction with phosphatidic acid . The Journal of Biological Chemistry . 277 . 31 . 28298–309 . Aug 2002 . 11994273 . 10.1074/jbc.M108353200 . 21243391 . free .
• Pryzwansky KB, Madden VJ . Type 4A cAMP-specific phosphodiesterase is stored in granules of human neutrophils and eosinophils . Cell and Tissue Research . 312 . 3 . 301–11 . Jun 2003 . 12764607 . 10.1007/s00441-003-0728-y . 8501967 .

Notes and References

1. Milatovich A, Bolger G, Michaeli T, Francke U . Chromosome localizations of genes for five cAMP-specific phosphodiesterases in man and mouse . Somatic Cell and Molecular Genetics . 20 . 2 . 75–86 . Mar 1994 . 8009369 . 10.1007/BF02290677 . 19182571 .
2. Web site: PDE4A phosphodiesterase 4A, cAMP-specific (Homo sapiens) . Entrez Gene . 2012-03-04 . 2012-04-02 .
3. Hansen RT, Conti M, ((Zhang H-T)) . 2014 . Mice deficient in phosphodiesterase-4A display anxiogenic-like behavior . Psychopharmacology . 231. 15. 2941–2954. 10.1007/s00213-014-3480-y . 24563185. 13542300 .
4. Rena G, Begg F, Ross A, MacKenzie C, McPhee I, Campbell L, Huston E, Sullivan M, Houslay MD . Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic amp-specific phosphodiesterase PDE4A10 . Molecular Pharmacology . 59 . 5 . 996–1011 . May 2001 . 11306681 . 10.1124/mol.59.5.996 .
5. Wallace DA, Johnston LA, Huston E, MacMaster D, Houslay TM, Cheung YF, Campbell L, Millen JE, Smith RA, Gall I, Knowles RG, Sullivan M, Houslay MD . Identification and characterization of PDE4A11, a novel, widely expressed long isoform encoded by the human PDE4A cAMP phosphodiesterase gene . Molecular Pharmacology . 67 . 6 . 1920–34 . Jun 2005 . 15738310 . 10.1124/mol.104.009423 . 1758221 .
6. Mackenzie KF, Topping EC, Bugaj-Gaweda B, Deng C, Cheung YF, Olsen AE, Stockard CR, High Mitchell L, Baillie GS, Grizzle WE, De Vivo M, Houslay MD, Wang D, Bolger GB . Human PDE4A8, a novel brain-expressed PDE4 cAMP-specific phosphodiesterase that has undergone rapid evolutionary change . The Biochemical Journal . 411 . 2 . 361–9 . Apr 2008 . 18095939 . 10.1042/BJ20071251 . 4337886 .