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PDE4A  -  phosphodiesterase 4A, cAMP-specific

Homo sapiens

Synonyms: DPDE2, PDE4, PDE46, cAMP-specific 3',5'-cyclic phosphodiesterase 4A
 
 
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Disease relevance of PDE4A

  • The main cAMP hydrolysing enzyme families of human MG-63 and SaOS-2 osteosarcoma cells were identified as PDE1 and PDE4 by assaying the PDE activity of Q-sepharose fractions and cell homogenates with selective inhibitors [1].
  • Our study highlights the importance of developing PDE4 inhibitors for the pharmacological management of infection-induced preterm labor [2].
  • The activity, expression and function of phosphodiesterase 4 (PDE 4) were investigated in the HMG human gingiva-derived malignant melanoma cell line [3].
  • Cyclic nucleotide PDE4 (phosphodiesterase 4) inhibitors are being developed as potent anti-inflammatory drugs for use in chronic lung diseases, but the complexity of the PDE4 family has hampered this process [4].
  • Recent reports, however, have indicated that specific PDE4 inhibitors were effective in treatment of experimental allergic encephalomyelitis, an animal model of multiple sclerosis [5].
 

Psychiatry related information on PDE4A

  • These data suggest further exploration of the combination of various PDE inhibitors and PGE1 in the pharmacologic treatment of erectile dysfunction and provide functional evidence for the presence of PDE 4 isoenzyme in human penile cavernosal cells [6].
  • Several lines of evidence indicate that targeting PDE4 with selective inhibitors may offer novel strategies in the treatment of age-related memory impairment and Alzheimer's disease [7].
  • With a growing body of work linking intracellular signaling pathways such as modulation of the cAMP second messenger system to a positive outcome following antidepressant therapy, the role that PDE4 inhibitors could play in the treatment of mood disorders has become more apparent [8].
  • In contrast, the potential use of PDE4 inhibitors to treat central nervous system disorders, such as major depressive disorders, has received less attention [8].
 

High impact information on PDE4A

  • Cardiac arrhythmias and dysfunction associated with PDE4 inhibition or deficiency were suppressed in mice harboring RyR2 that cannot be PKA phosphorylated [9].
  • The co-receptor CD28 enhances signalling through the T-cell receptor by recruiting a PDE4/beta-arrestin complex, which then attenuates PKA phosphorylation of Csk [10].
  • Knockdown of specific membrane-associated AKAPs using RNAi identified gravin (AKAP250) as the central organizer of the PDE4 complex [11].
  • A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates [12].
  • We describe a family of potent PDE4 inhibitors discovered using an efficient method for scaffold-based drug design [12].
 

Chemical compound and disease context of PDE4A

  • V11294 caused relaxation of guinea pig isolated trachea and inhibited allergen-induced bronchoconstriction and eosinophilia in guinea pigs at doses of 1 and 3 mg/kg, p.o. In ferrets, V11294 was not emetogenic at doses up to 30 mg/kg, p.o., despite plasma concentration reaching 10-fold the IC(50) for PDE4 [13].
  • Both models proofed to be well suited for the characterisation of the antiinflammatory properties of new chemical entities.In diluted human blood and dispersed human nasal polyp cells the induced TNF release was most potently suppressed by selective PDE4 inhibitors [14].
  • Inhibitors of phosphodiesterase type 4 (PDE4) act by increasing intracellular concentrations of cyclic AMP, which has a broad range of anti-inflammatory effects on various key effector cells involved in asthma and chronic obstructive pulmonary disease (COPD) [15].
  • The results of the present study suggest that use of agents such as rolipram that inhibit PDE4 may have a therapeutic role in treatment of acute lung injury, since we have shown that it is effective in attenuation of neutrophil activation even after sequestration [16].
  • While cilomilast and roflumilast have low emetic potential they are not free from emesis and various strategies are being investigated in the hope of developing a PDE4 inhibitor without this adverse effect [17].
 

Biological context of PDE4A

  • This leads to the down-regulation of a novel PDE4A splice variant and the induction of PDE4D1 and PDE4D2 splice variants, leading to a net increase in the total PDE4 activity of Jurkat T-cells [18].
  • 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 [19].
  • The affinity for Mg2+ varied by less than 4-fold between long and catalytic-domain forms of PDE4A and 4B [20].
  • In contrast, PDE4A isoenzymes do not provide substrates for C-terminal catalytic unit phosphorylation by Erk2 [21].
  • 4. In both sets of experiments, mean IC50 values were significantly correlated with compound potency against the catalytic activity of recombinant human PDE4A or PDE4B when analysed by either linear regression of log IC50 values or by Spearman's rank-order correlation [22].
 

Anatomical context of PDE4A

  • Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant [18].
  • It is suggested that the PDE4A splice variant RD1 contains a membrane-association signal which allows the targeted expression of RD1 within the Golgi complex of these human follicular thyroid carcinoma cell lines [23].
  • Intracellular localization of the PDE4A cAMP-specific phosphodiesterase splice variant RD1 (RNPDE4A1A) in stably transfected human thyroid carcinoma FTC cell lines [23].
  • In CD4 and CD8 lymphocytes PDE4A, PDE4B and PDE4D were detected, with no significant differences observed between healthy and asthmatic groups [24].
  • AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa [25].
 

Associations of PDE4A with chemical compounds

 

Physical interactions of PDE4A

  • Overlay studies with PDE4D5 scanning peptide array libraries showed that RACK1 and beta-arrestin interact at overlapping sites within the unique N-terminal region of PDE4D5 and at distinct sites within the conserved PDE4 catalytic domain [30].
 

Enzymatic interactions of PDE4A

  • Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases [21].
 

Co-localisations of PDE4A

  • Particulate pde46 co-localized with LYN kinase in COS7 cells [31].
 

Regulatory relationships of PDE4A

 

Other interactions of PDE4A

  • Further analysis of MTG/PDE association illustrated that PDE4A and PDE7A bind residues 1-344 of MTG16b [36].
  • Purified LYN SH3 and human PDE4A LR2 could be co-immunoprecipitated, indicating a direct interaction [31].
  • The PDE4 selective inhibitor, rolipram, inhibited immunopurified PDE4B and PDE4D activities similarly, with IC(50) values of approx. 130 nM and 240 nM respectively [26].
  • The specific activities of the total PDE4A, PDE4B and PDE4D activities were 0.63+/-0.09, 8.8+/-0.2 and 34.4+/-2.9 pmol/min per mg of protein respectively [26].
  • Eight amino acid residues that are highly conserved in the cAMP-hydrolysing phosphodiesterases (PDE1, PDE3, PDE4, PDE7, PDE8) and that did not show any homologies to the cGMP-specific phosphodiesterases (PDE5, PDE6, PDE9) were selected from these alignments [27].
 

Analytical, diagnostic and therapeutic context of PDE4A

References

  1. Dexamethasone down-regulates cAMP-phosphodiesterase in human osteosarcoma cells. Ahlström, M., Pekkinen, M., Huttunen, M., Lamberg-Allardt, C. Biochem. Pharmacol. (2005) [Pubmed]
  2. Anti-inflammatory and utero-relaxant effects in human myometrium of new generation phosphodiesterase 4 inhibitors. Oger, S., Méhats, C., Barnette, M.S., Ferré, F., Cabrol, D., Leroy, M.J. Biol. Reprod. (2004) [Pubmed]
  3. A role for cyclic nucleotide phosphodiesterase 4 in regulation of the growth of human malignant melanoma cells. Narita, M., Murata, T., Shimizu, K., Nakagawa, T., Sugiyama, T., Inui, M., Hiramoto, K., Tagawa, T. Oncol. Rep. (2007) [Pubmed]
  4. Splice variants of the cyclic nucleotide phosphodiesterase PDE4D are differentially expressed and regulated in rat tissue. Richter, W., Jin, S.L., Conti, M. Biochem. J. (2005) [Pubmed]
  5. Differential expression of cyclic nucleotide phosphodiesterase 3 and 4 activities in human T cell clones specific for myelin basic protein. Ekholm, D., Hemmer, B., Gao, G., Vergelli, M., Martin, R., Manganiello, V. J. Immunol. (1997) [Pubmed]
  6. Potentiation of erectile response and cAMP accumulation by combination of prostaglandin E1 and rolipram, a selective inhibitor of the type 4 phosphodiesterase (PDE 4). Bivalacqua, T.J., Champion, H.C., Rajasekaran, M., Sikka, S.C., Kadowitz, P.J., Doherty, P.C., Hellstrom, W.J. J. Urol. (1999) [Pubmed]
  7. Selective Phosphodiesterase (PDE)-4 Inhibitors : A Novel Approach to Treating Memory Deficit? Ghavami, A., Hirst, W.D., Novak, T.J. Drugs in R&D. (2006) [Pubmed]
  8. The potential of phosphodiesterase 4 inhibitors for the treatment of depression: opportunities and challenges. Renau, T.E. Current opinion in investigational drugs (London, England : 2000) (2004) [Pubmed]
  9. Phosphodiesterase 4D deficiency in the ryanodine-receptor complex promotes heart failure and arrhythmias. Lehnart, S.E., Wehrens, X.H., Reiken, S., Warrier, S., Belevych, A.E., Harvey, R.D., Richter, W., Jin, S.L., Conti, M., Marks, A.R. Cell (2005) [Pubmed]
  10. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Baillie, G.S., Houslay, M.D. Curr. Opin. Cell Biol. (2005) [Pubmed]
  11. An anchored PKA and PDE4 complex regulates subplasmalemmal cAMP dynamics. Willoughby, D., Wong, W., Schaack, J., Scott, J.D., Cooper, D.M. EMBO J. (2006) [Pubmed]
  12. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Card, G.L., Blasdel, L., England, B.P., Zhang, C., Suzuki, Y., Gillette, S., Fong, D., Ibrahim, P.N., Artis, D.R., Bollag, G., Milburn, M.V., Kim, S.H., Schlessinger, J., Zhang, K.Y. Nat. Biotechnol. (2005) [Pubmed]
  13. Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294. Gale, D.D., Hofer, P., Spina, D., Seeds, E.A., Banner, K.H., Harrison, S., Douglas, G., Matsumoto, T., Page, C.P., Wong, R.H., Jordan, S., Smith, F., Banik, N., Halushka, P.V., Cavalla, D., Rotshteyn, Y., Kyle, D.J., Burch, R.M., Chasin, M. Pulmonary pharmacology & therapeutics. (2003) [Pubmed]
  14. Modulation of TNF and GM-CSF release from dispersed human nasal polyp cells and human whole blood by inhibitors of different PDE isoenzymes and glucocorticoids. Marx, D., Tassabehji, M., Heer, S., Hüttenbrink, K.B., Szelenyi, I. Pulmonary pharmacology & therapeutics. (2002) [Pubmed]
  15. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lipworth, B.J. Lancet (2005) [Pubmed]
  16. Suppression of acute lung injury in mice by an inhibitor of phosphodiesterase type 4. Miotla, J.M., Teixeira, M.M., Hellewell, P.G. Am. J. Respir. Cell Mol. Biol. (1998) [Pubmed]
  17. Phosphodiesterase-4 inhibitors in the treatment of inflammatory lung disease. Spina, D. Drugs (2003) [Pubmed]
  18. Challenge of human Jurkat T-cells with the adenylate cyclase activator forskolin elicits major changes in cAMP phosphodiesterase (PDE) expression by up-regulating PDE3 and inducing PDE4D1 and PDE4D2 splice variants as well as down-regulating a novel PDE4A splice variant. Erdogan, S., Houslay, M.D. Biochem. J. (1997) [Pubmed]
  19. 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. Sullivan, M., Rena, G., Begg, F., Gordon, L., Olsen, A.S., Houslay, M.D. Biochem. J. (1998) [Pubmed]
  20. Comparison of recombinant human PDE4 isoforms: interaction with substrate and inhibitors. Saldou, N., Obernolte, R., Huber, A., Baecker, P.A., Wilhelm, R., Alvarez, R., Li, B., Xia, L., Callan, O., Su, C., Jarnagin, K., Shelton, E.R. Cell. Signal. (1998) [Pubmed]
  21. Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Baillie, G.S., MacKenzie, S.J., McPhee, I., Houslay, M.D. Br. J. Pharmacol. (2000) [Pubmed]
  22. Suppression of human inflammatory cell function by subtype-selective PDE4 inhibitors correlates with inhibition of PDE4A and PDE4B. Manning, C.D., Burman, M., Christensen, S.B., Cieslinski, L.B., Essayan, D.M., Grous, M., Torphy, T.J., Barnette, M.S. Br. J. Pharmacol. (1999) [Pubmed]
  23. Intracellular localization of the PDE4A cAMP-specific phosphodiesterase splice variant RD1 (RNPDE4A1A) in stably transfected human thyroid carcinoma FTC cell lines. Pooley, L., Shakur, Y., Rena, G., Houslay, M.D. Biochem. J. (1997) [Pubmed]
  24. Identification and quantification of phosphodiesterase 4 subtypes in CD4 and CD8 lymphocytes from healthy and asthmatic subjects. Landells, L.J., Szilagy, C.M., Jones, N.A., Banner, K.H., Allen, J.M., Doherty, A., O'Connor, B.J., Spina, D., Page, C.P. Br. J. Pharmacol. (2001) [Pubmed]
  25. AKAP3 selectively binds PDE4A isoforms in bovine spermatozoa. Bajpai, M., Fiedler, S.E., Huang, Z., Vijayaraghavan, S., Olson, G.E., Livera, G., Conti, M., Carr, D.W. Biol. Reprod. (2006) [Pubmed]
  26. Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells. MacKenzie, S.J., Houslay, M.D. Biochem. J. (2000) [Pubmed]
  27. Identification of substrate specificity determinants in human cAMP-specific phosphodiesterase 4A by single-point mutagenesis. Richter, W., Unciuleac, L., Hermsdorf, T., Kronbach, T., Dettmer, D. Cell. Signal. (2001) [Pubmed]
  28. Selective inhibition of purified human phosphodiesterase 4A expressed in yeast cell GL62 by ciclamilast, piclamilast, and rolipram. Chen, J.C., Chen, J.Q., Xie, Q.M., Zhu, Y.L. Acta Pharmacol. Sin. (2004) [Pubmed]
  29. Diazepam and rolipram differentially inhibit cyclic AMP-specific phosphodiesterases PDE4A1 and PDE4B3 in the mouse. Cherry, J.A., Thompson, B.E., Pho, V. Biochim. Biophys. Acta (2001) [Pubmed]
  30. Scanning peptide array analyses identify overlapping binding sites for the signalling scaffold proteins, beta-arrestin and RACK1, in cAMP-specific phosphodiesterase PDE4D5. Bolger, G.B., Baillie, G.S., Li, X., Lynch, M.J., Herzyk, P., Mohamed, A., Mitchell, L.H., McCahill, A., Hundsrucker, C., Klussmann, E., Adams, D.R., Houslay, M.D. Biochem. J. (2006) [Pubmed]
  31. 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. McPhee, I., Yarwood, S.J., Scotland, G., Huston, E., Beard, M.B., Ross, A.H., Houslay, E.S., Houslay, M.D. J. Biol. Chem. (1999) [Pubmed]
  32. Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Heystek, H.C., Thierry, A.C., Soulard, P., Moulon, C. Int. Immunol. (2003) [Pubmed]
  33. Phosphodiesterase-4 influences the PKA phosphorylation status and membrane translocation of G-protein receptor kinase 2 (GRK2) in HEK-293beta2 cells and cardiac myocytes. Li, X., Huston, E., Lynch, M.J., Houslay, M.D., Baillie, G.S. Biochem. J. (2006) [Pubmed]
  34. Regulatory roles of adenylate cyclase and cyclic nucleotide phosphodiesterases 1 and 4 in interleukin-13 production by activated human T cells. Kanda, N., Watanabe, S. Biochem. Pharmacol. (2001) [Pubmed]
  35. Phosphodiesterase 4 inhibition synergizes with relaxin signaling to promote decidualization of human endometrial stromal cells. Bartsch, O., Bartlick, B., Ivell, R. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  36. A-kinase anchoring proteins interact with phosphodiesterases in T lymphocyte cell lines. Asirvatham, A.L., Galligan, S.G., Schillace, R.V., Davey, M.P., Vasta, V., Beavo, J.A., Carr, D.W. J. Immunol. (2004) [Pubmed]
  37. Prolonged beta adrenoceptor stimulation up-regulates cAMP phosphodiesterase activity in human monocytes by increasing mRNA and protein for phosphodiesterases 4A and 4B. Manning, C.D., McLaughlin, M.M., Livi, G.P., Cieslinski, L.B., Torphy, T.J., Barnette, M.S. J. Pharmacol. Exp. Ther. (1996) [Pubmed]
  38. L-arginine and phosphodiesterase (PDE) inhibitors counteract fibrosis in the Peyronie's fibrotic plaque and related fibroblast cultures. Valente, E.G., Vernet, D., Ferrini, M.G., Qian, A., Rajfer, J., Gonzalez-Cadavid, N.F. Nitric Oxide (2003) [Pubmed]
  39. Type 4A cAMP-specific phosphodiesterase is stored in granules of human neutrophils and eosinophils. Pryzwansky, K.B., Madden, V.J. Cell Tissue Res. (2003) [Pubmed]
 
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