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Gene Review

PDE4D  -  phosphodiesterase 4D, cAMP-specific

Homo sapiens

Synonyms: ACRDYS2, DPDE3, HSPDE4D, PDE43, PDE4DN2, ...
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Disease relevance of PDE4D


High impact information on PDE4D

  • We show that PDE4D gene inactivation in mice results in a progressive cardiomyopathy, accelerated heart failure after myocardial infarction, and cardiac arrhythmias [4].
  • By using pharmacological and genetic manipulation of phosphodiesterases (PDEs), we demonstrate that compartmentalized PDE4B and PDE4D are responsible for selectively modulating the concentration of cAMP in individual subcellular compartments [6].
  • 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 [7].
  • Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites [7].
  • Recent studies in Iceland identified risk polymorphisms in two putative candidate genes for ischemic stroke: phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) [8].

Chemical compound and disease context of PDE4D


Biological context of PDE4D

  • Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM [10].
  • Addition of UCR2 to the catalytic-domain form of PDE4D restored all the lost sensitivities [11].
  • The model for PDE4D is also discussed in relation to changes in the activation curve for Mg2+ and sensitivity to RS-25344 that accompany phosphorylation of the long form by protein kinase A [11].
  • The amount of message for PDE4A and PDE4B appeared to increase upon up-regulation, whereas mRNA for PDE4D was not detected in treated cells [12].
  • Although no evidence supported linkage of ischemic stroke with either of the two candidate genes, single-nucleotide polymorphisms and haplotypic associations were observed between PDE4D and ischemic stroke [8].

Anatomical context of PDE4D


Associations of PDE4D with chemical compounds

  • Isoproterenol challenge of Hek-B2 cells causes a transient recruitment of the endogenous PDE4D isoforms found in these cells, namely PDE4D3 and PDE4D5, to the membrane fraction [13].
  • RESULTS: Rolipram increased levels of PDE4B and, to a variable extent, PDE4D [18].
  • SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM [10].
  • Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma [10].
  • ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions [19].

Physical interactions of PDE4D


Regulatory relationships of PDE4D

  • The PKA phosphorylation status of the beta(2)AR is enhanced markedly when cells are treated with the selective PDE4-inhibitor rolipram or when they are transfected with a catalytically inactive PDE4D mutant (PDE4D5-D556A) that competitively inhibits isoprenaline-stimulated recruitment of native PDE4 to the beta(2)AR [21].
  • METHODS: Three polymorphisms in PDE4D gene were analyzed in 200 patients of ischemic stroke and 250 controls of Pakistani origin using polymerase chain reaction-restriction fragment length polymorphism method [22].
  • Thus, PDE3B and PDE4D can be added to the list of genes regulated by insulin and cAMP-increasing hormones [23].
  • The observations that expression of PDE4D transcripts were selectively increased by cAMP and that inhibition of protein kinase A by H89 to potentially block negative feedback regulation enhanced the relaxin/rolipram-mediated cAMP accumulation lead to a complex picture of cAMP regulation in these cells [24].

Other interactions of PDE4D

  • 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 [25].
  • Isoprenaline-stimulated membrane recruitment of PDE4D is ablated upon beta arrestin knockdown [26].
  • Gene expression for PDE4D and PDE4C was significantly up-regulated during in vitro decidualization [27].
  • By RT-PCR, increments of PDE4D and 4C messenger ribonucleic acids were found in the ATAs with mutant TSHR or Gsalpha, whereas messenger ribonucleic acids encoding other cAMP-specific PDEs were not significantly increased [28].
  • Together, these data show reciprocal regulation of PDE1C and PDE4D by PKA, which represents a novel scheme for plasticity in intracellular signalling [29].

Analytical, diagnostic and therapeutic context of PDE4D


  1. Genotype and haplotype association study of the STRK1 region on 5q12 among Japanese: a case-control study. Nakayama, T., Asai, S., Sato, N., Soma, M. Stroke (2006) [Pubmed]
  2. Familial aggregation, the PDE4D gene, and ischemic stroke in a genetically isolated population. van Rijn, M.J., Slooter, A.J., Schut, A.F., Isaacs, A., Aulchenko, Y.S., Snijders, P.J., Kappelle, L.J., van Swieten, J.C., Oostra, B.A., van Duijn, C.M. Neurology (2005) [Pubmed]
  3. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lipworth, B.J. Lancet (2005) [Pubmed]
  4. 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]
  5. Association of phosphodiesterase 4D gene polymorphisms with chronic obstructive pulmonary disease: Relationship to interleukin 13 gene polymorphism. Homma, S., Sakamoto, T., Hegab, A.E., Saitoh, W., Nomura, A., Ishii, Y., Morishima, Y., Iizuka, T., Kiwamoto, T., Matsuno, Y., Massoud, H.H., Massoud, H.M., Hassanein, K.M., Sekizawa, K. Int. J. Mol. Med. (2006) [Pubmed]
  6. PGE1 stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases. Terrin, A., Di Benedetto, G., Pertegato, V., Cheung, Y.F., Baillie, G., Lynch, M.J., Elvassore, N., Prinz, A., Herberg, F.W., Houslay, M.D., Zaccolo, M. J. Cell Biol. (2006) [Pubmed]
  7. 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]
  8. Phosphodiesterase 4D and 5-lipoxygenase activating protein in ischemic stroke. Meschia, J.F., Brott, T.G., Brown, R.D., Crook, R., Worrall, B.B., Kissela, B., Brown, W.M., Rich, S.S., Case, L.D., Evans, E.W., Hague, S., Singleton, A., Hardy, J. Ann. Neurol. (2005) [Pubmed]
  9. Role of FLAP and PDE4D in Myocardial Infarction and Stroke: Target Discovery and Future Treatment Options. Hakonarson, H. Current treatment options in cardiovascular medicine. (2006) [Pubmed]
  10. Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors. Hersperger, R., Bray-French, K., Mazzoni, L., Müller, T. J. Med. Chem. (2000) [Pubmed]
  11. 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]
  12. 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]
  13. The unique amino-terminal region of the PDE4D5 cAMP phosphodiesterase isoform confers preferential interaction with beta-arrestins. Bolger, G.B., McCahill, A., Huston, E., Cheung, Y.F., McSorley, T., Baillie, G.S., Houslay, M.D. J. Biol. Chem. (2003) [Pubmed]
  14. Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter. Le Jeune, I.R., Shepherd, M., Van Heeke, G., Houslay, M.D., Hall, I.P. J. Biol. Chem. (2002) [Pubmed]
  15. Differential regulation of human antigen-specific Th1 and Th2 lymphocyte responses by isozyme selective cyclic nucleotide phosphodiesterase inhibitors. Essayan, D.M., Kagey-Sobotka, A., Lichtenstein, L.M., Huang, S.K. J. Pharmacol. Exp. Ther. (1997) [Pubmed]
  16. Phosphodiesterases 4D and 7A splice variants in the response of HUVEC cells to TNF-alpha(1). Miró, X., Casacuberta, J.M., Gutiérrez-López, M.D., de Landázuri, M.O., Puigdomènech, P. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  17. Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. Verde, I., Pahlke, G., Salanova, M., Zhang, G., Wang, S., Coletti, D., Onuffer, J., Jin, S.L., Conti, M. J. Biol. Chem. (2001) [Pubmed]
  18. Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia. Moon, E., Lee, R., Near, R., Weintraub, L., Wolda, S., Lerner, A. Clin. Cancer Res. (2002) [Pubmed]
  19. ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. MacKenzie, S.J., Baillie, G.S., McPhee, I., Bolger, G.B., Houslay, M.D. J. Biol. Chem. (2000) [Pubmed]
  20. 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]
  21. beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Baillie, G.S., Sood, A., McPhee, I., Gall, I., Perry, S.J., Lefkowitz, R.J., Houslay, M.D. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  22. Association of phosphodiesterase 4D gene with ischemic stroke in a Pakistani population. Saleheen, D., Bukhari, S., Haider, S.R., Nazir, A., Khanum, S., Shafqat, S., Anis, M.K., Frossard, P. Stroke (2005) [Pubmed]
  23. Long-term regulation of cyclic nucleotide phosphodiesterase type 3B and 4 in 3T3-L1 adipocytes. Oknianska, A., Zmuda-Trzebiatowska, E., Manganiello, V., Degerman, E. Biochem. Biophys. Res. Commun. (2007) [Pubmed]
  24. Relaxin and phosphodiesterases collaborate during decidualization. Bartscha, O., Ivell, R. Ann. N. Y. Acad. Sci. (2004) [Pubmed]
  25. 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]
  26. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with beta arrestin to control the protein kinase A/AKAP79-mediated switching of the beta2-adrenergic receptor to activation of ERK in HEK293B2 cells. Lynch, M.J., Baillie, G.S., Mohamed, A., Li, X., Maisonneuve, C., Klussmann, E., van Heeke, G., Houslay, M.D. J. Biol. Chem. (2005) [Pubmed]
  27. 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]
  28. Induction of specific phosphodiesterase isoforms by constitutive activation of the cAMP pathway in autonomous thyroid adenomas. Persani, L., Lania, A., Alberti, L., Romoli, R., Mantovani, G., Filetti, S., Spada, A., Conti, M. J. Clin. Endocrinol. Metab. (2000) [Pubmed]
  29. Reciprocal regulation of calcium dependent and calcium independent cyclic AMP hydrolysis by protein phosphorylation. Ang, K.L., Antoni, F.A. J. Neurochem. (2002) [Pubmed]
  30. Phosphodiesterase 4D forms a cAMP diffusion barrier at the apical membrane of the airway epithelium. Barnes, A.P., Livera, G., Huang, P., Sun, C., O'Neal, W.K., Conti, M., Stutts, M.J., Milgram, S.L. J. Biol. Chem. (2005) [Pubmed]
  31. Association of Phosphodiesterase 4D with ischemic stroke: a population-based case-control study. Woo, D., Kaushal, R., Kissela, B., Sekar, P., Wolujewicz, M., Pal, P., Alwell, K., Haverbusch, M., Ewing, I., Miller, R., Kleindorfer, D., Flaherty, M., Chakraborty, R., Deka, R., Broderick, J. Stroke (2006) [Pubmed]
  32. 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]
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