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. 2003 Feb 15;370(Pt 1):1–18. doi: 10.1042/BJ20021698

PDE4 cAMP phosphodiesterases: modular enzymes that orchestrate signalling cross-talk, desensitization and compartmentalization.

Miles D Houslay 1, David R Adams 1
PMCID: PMC1223165  PMID: 12444918

Abstract

cAMP is a second messenger that controls many key cellular functions. The only way to inactivate cAMP is to degrade it through the action of cAMP phosphodiesterases (PDEs). PDEs are thus poised to play a key regulatory role. PDE4 cAMP-specific phosphodiesterases appear to have specific functions with selective inhibitors serving as potent anti-inflammatory agents. The recent elucidation of the structure of the PDE4 catalytic unit allows for molecular insight into the mode of catalysis as well as substrate and inhibitor selectivity. The four PDE4 genes encode over 16 isoforms, each of which is characterized by a unique N-terminal region. PDE4 isoforms play a pivotal role in controlling functionally and spatially distinct pools of cAMP by virtue of their unique intracellular targeting. Targeting occurs by association with proteins, such as arrestins, SRC family tyrosyl kinases, A-kinase anchoring proteins ('AKAPs') and receptor for activated C kinase 1 ('RACK1'), and, in the case of isoform PDE4A1, by a specific interaction (TAPAS-1) with phosphatidic acid. PDE4 isoforms are 'designed' to be regulated by extracellular-signal-related protein kinase (ERK), which binds to anchor sites on the PDE4 catalytic domain that it phosphorylates. The upstream conserved region 1 (UCR1) and 2 (UCR2) modules that abut the PDE4 catalytic unit confer regulatory functions by orchestrating the functional outcome of phosphorylation by cAMP-dependent protein kinase ('PKA') and ERK. PDE4 enzymes stand at a crossroads that allows them to integrate various signalling pathways with that of cAMP in spatially distinct compartments.

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Selected References

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  1. Ahmad F., Gao G., Wang L. M., Landstrom T. R., Degerman E., Pierce J. H., Manganiello V. C. IL-3 and IL-4 activate cyclic nucleotide phosphodiesterases 3 (PDE3) and 4 (PDE4) by different mechanisms in FDCP2 myeloid cells. J Immunol. 1999 Apr 15;162(8):4864–4875. [PubMed] [Google Scholar]
  2. Baillie G. S., MacKenzie S. J., McPhee I., Houslay M. D. Sub-family selective actions in the ability of Erk2 MAP kinase to phosphorylate and regulate the activity of PDE4 cyclic AMP-specific phosphodiesterases. Br J Pharmacol. 2000 Oct;131(4):811–819. doi: 10.1038/sj.bjp.0703636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baillie G., MacKenzie S. J., Houslay M. D. Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). Mol Pharmacol. 2001 Nov;60(5):1100–1111. doi: 10.1124/mol.60.5.1100. [DOI] [PubMed] [Google Scholar]
  4. Baillie George S., Huston Elaine, Scotland Grant, Hodgkin Matt, Gall Irene, Peden Alex H., MacKenzie Carolynn, Houslay Emma S., Currie Richard, Pettitt Trevor R. 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. J Biol Chem. 2002 May 6;277(31):28298–28309. doi: 10.1074/jbc.M108353200. [DOI] [PubMed] [Google Scholar]
  5. Barnette M. S., Underwood D. C. New phosphodiesterase inhibitors as therapeutics for the treatment of chronic lung disease. Curr Opin Pulm Med. 2000 Mar;6(2):164–169. doi: 10.1097/00063198-200003000-00014. [DOI] [PubMed] [Google Scholar]
  6. Beard M. B., O'Connell J. C., Bolger G. B., Houslay M. D. The unique N-terminal domain of the cAMP phosphodiesterase PDE4D4 allows for interaction with specific SH3 domains. FEBS Lett. 1999 Oct 22;460(1):173–177. doi: 10.1016/s0014-5793(99)01335-6. [DOI] [PubMed] [Google Scholar]
  7. Beard M. B., Olsen A. E., Jones R. E., Erdogan S., Houslay M. D., Bolger G. B. UCR1 and UCR2 domains unique to the cAMP-specific phosphodiesterase family form a discrete module via electrostatic interactions. J Biol Chem. 2000 Apr 7;275(14):10349–10358. doi: 10.1074/jbc.275.14.10349. [DOI] [PubMed] [Google Scholar]
  8. Beard Matthew B., Huston Elaine, Campbell Lachlan, Gall Irene, McPhee Ian, Yarwood Stephen, Scotland Grant, Houslay Miles D. In addition to the SH3 binding region, multiple regions within the N-terminal noncatalytic portion of the cAMP-specific phosphodiesterase, PDE4A5, contribute to its intracellular targeting. Cell Signal. 2002 May;14(5):453–465. doi: 10.1016/s0898-6568(01)00264-9. [DOI] [PubMed] [Google Scholar]
  9. Beavo Joseph A., Brunton Laurence L. Cyclic nucleotide research -- still expanding after half a century. Nat Rev Mol Cell Biol. 2002 Sep;3(9):710–718. doi: 10.1038/nrm911. [DOI] [PubMed] [Google Scholar]
  10. Bolger G. B., Erdogan S., Jones R. E., Loughney K., Scotland G., Hoffmann R., Wilkinson I., Farrell C., Houslay M. D. Characterization of five different proteins produced by alternatively spliced mRNAs from the human cAMP-specific phosphodiesterase PDE4D gene. Biochem J. 1997 Dec 1;328(Pt 2):539–548. doi: 10.1042/bj3280539. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Bolger G. B., Rodgers L., Riggs M. Differential CNS expression of alternative mRNA isoforms of the mammalian genes encoding cAMP-specific phosphodiesterases. Gene. 1994 Nov 18;149(2):237–244. doi: 10.1016/0378-1119(94)90155-4. [DOI] [PubMed] [Google Scholar]
  12. 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. Mol Cell Biol. 1993 Oct;13(10):6558–6571. doi: 10.1128/mcb.13.10.6558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Bolger Graeme B., McCahill Angela, Yarwood Stephen J., Steele Michael R., Warwicker Jim, Houslay Miles D. Delineation of RAID1, the RACK1 interaction domain located within the unique N-terminal region of the cAMP-specific phosphodiesterase, PDE4D5. BMC Biochem. 2002 Aug 23;3:24–24. doi: 10.1186/1471-2091-3-24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Burnouf Catherine, Pruniaux Marie-Pierre. Recent advances in PDE4 inhibitors as immunoregulators and anti-inflammatory drugs. Curr Pharm Des. 2002;8(14):1255–1296. doi: 10.2174/1381612023394665. [DOI] [PubMed] [Google Scholar]
  15. Chang Y. H., Conti M., Lee Y. C., Lai H. L., Ching Y. H., Chern Y. Activation of phosphodiesterase IV during desensitization of the A2A adenosine receptor-mediated cyclic AMP response in rat pheochromocytoma (PC12) cells. J Neurochem. 1997 Sep;69(3):1300–1309. doi: 10.1046/j.1471-4159.1997.69031300.x. [DOI] [PubMed] [Google Scholar]
  16. Colledge M., Scott J. D. AKAPs: from structure to function. Trends Cell Biol. 1999 Jun;9(6):216–221. doi: 10.1016/s0962-8924(99)01558-5. [DOI] [PubMed] [Google Scholar]
  17. Conti M., Jin S. L. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 1999;63:1–38. doi: 10.1016/s0079-6603(08)60718-7. [DOI] [PubMed] [Google Scholar]
  18. Davis R. L., Davidson N. The memory gene dunce+ encodes a remarkable set of RNAs with internal heterogeneity. Mol Cell Biol. 1986 May;6(5):1464–1470. doi: 10.1128/mcb.6.5.1464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Davis R. L., Takayasu H., Eberwine M., Myres J. Cloning and characterization of mammalian homologs of the Drosophila dunce+ gene. Proc Natl Acad Sci U S A. 1989 May;86(10):3604–3608. doi: 10.1073/pnas.86.10.3604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Degerman E., Smith C. J., Tornqvist H., Vasta V., Belfrage P., Manganiello V. C. Evidence that insulin and isoprenaline activate the cGMP-inhibited low-Km cAMP phosphodiesterase in rat fat cells by phosphorylation. Proc Natl Acad Sci U S A. 1990 Jan;87(2):533–537. doi: 10.1073/pnas.87.2.533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. DiSanto M. E., Glaser K. B., Heaslip R. J. Phospholipid regulation of a cyclic AMP-specific phosphodiesterase (PDE4) from U937 cells. Cell Signal. 1995 Nov;7(8):827–835. doi: 10.1016/0898-6568(95)02010-1. [DOI] [PubMed] [Google Scholar]
  22. Diviani D., Scott J. D. AKAP signaling complexes at the cytoskeleton. J Cell Sci. 2001 Apr;114(Pt 8):1431–1437. doi: 10.1242/jcs.114.8.1431. [DOI] [PubMed] [Google Scholar]
  23. Dodge K. L., Khouangsathiene S., Kapiloff M. S., Mouton R., Hill E. V., Houslay M. D., Langeberg L. K., Scott J. D. mAKAP assembles a protein kinase A/PDE4 phosphodiesterase cAMP signaling module. EMBO J. 2001 Apr 17;20(8):1921–1930. doi: 10.1093/emboj/20.8.1921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Doherty A. M. Phosphodiesterase 4 inhibitors as novel anti-inflammatory agents. Curr Opin Chem Biol. 1999 Aug;3(4):466–473. doi: 10.1016/S1367-5931(99)80068-4. [DOI] [PubMed] [Google Scholar]
  25. Dousa T. P. Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int. 1999 Jan;55(1):29–62. doi: 10.1046/j.1523-1755.1999.00233.x. [DOI] [PubMed] [Google Scholar]
  26. Dym Orly, Xenarios Ioannis, Ke Hengming, Colicelli John. Molecular docking of competitive phosphodiesterase inhibitors. Mol Pharmacol. 2002 Jan;61(1):20–25. doi: 10.1124/mol.61.1.20. [DOI] [PubMed] [Google Scholar]
  27. Ekholm D., Belfrage P., Manganiello V., Degerman E. Protein kinase A-dependent activation of PDE4 (cAMP-specific cyclic nucleotide phosphodiesterase) in cultured bovine vascular smooth muscle cells. Biochim Biophys Acta. 1997 Mar 27;1356(1):64–70. doi: 10.1016/s0167-4889(96)00159-0. [DOI] [PubMed] [Google Scholar]
  28. El Bawab S., Macovschi O., Sette C., Conti M., Lagarde M., Nemoz G., Prigent A. F. Selective stimulation of a cAMP-specific phosphodiesterase (PDE4A5) isoform by phosphatidic acid molecular species endogenously formed in rat thymocytes. Eur J Biochem. 1997 Aug 1;247(3):1151–1157. doi: 10.1111/j.1432-1033.1997.01151.x. [DOI] [PubMed] [Google Scholar]
  29. Essayan D. M. Cyclic nucleotide phosphodiesterase (PDE) inhibitors and immunomodulation. Biochem Pharmacol. 1999 May 1;57(9):965–973. doi: 10.1016/s0006-2952(98)00331-1. [DOI] [PubMed] [Google Scholar]
  30. Exton J. H. Regulation of phospholipase D. Biochim Biophys Acta. 1999 Jul 30;1439(2):121–133. doi: 10.1016/s1388-1981(99)00089-x. [DOI] [PubMed] [Google Scholar]
  31. Feliciello A., Gottesman M. E., Avvedimento E. V. The biological functions of A-kinase anchor proteins. J Mol Biol. 2001 Apr 27;308(2):99–114. doi: 10.1006/jmbi.2001.4585. [DOI] [PubMed] [Google Scholar]
  32. Francis S. H., Colbran J. L., McAllister-Lucas L. M., Corbin J. D. Zinc interactions and conserved motifs of the cGMP-binding cGMP-specific phosphodiesterase suggest that it is a zinc hydrolase. J Biol Chem. 1994 Sep 9;269(36):22477–22480. [PubMed] [Google Scholar]
  33. Ghosh S., Strum J. C., Sciorra V. A., Daniel L., Bell R. M. Raf-1 kinase possesses distinct binding domains for phosphatidylserine and phosphatidic acid. Phosphatidic acid regulates the translocation of Raf-1 in 12-O-tetradecanoylphorbol-13-acetate-stimulated Madin-Darby canine kidney cells. J Biol Chem. 1996 Apr 5;271(14):8472–8480. doi: 10.1074/jbc.271.14.8472. [DOI] [PubMed] [Google Scholar]
  34. Giembycz M. A. Development status of second generation PDE4 inhibitors for asthma and COPD: the story so far. Monaldi Arch Chest Dis. 2002 Feb;57(1):48–64. [PubMed] [Google Scholar]
  35. Giembycz M. A. Phosphodiesterase 4 inhibitors and the treatment of asthma: where are we now and where do we go from here? Drugs. 2000 Feb;59(2):193–212. doi: 10.2165/00003495-200059020-00004. [DOI] [PubMed] [Google Scholar]
  36. Grange M., Sette C., Cuomo M., Conti M., Lagarde M., Prigent A. F., Némoz G. The cAMP-specific phosphodiesterase PDE4D3 is regulated by phosphatidic acid binding. Consequences for cAMP signaling pathway and characterization of a phosphatidic acid binding site. J Biol Chem. 2000 Oct 27;275(43):33379–33387. doi: 10.1074/jbc.M006329200. [DOI] [PubMed] [Google Scholar]
  37. Hansen G., Jin S., Umetsu D. T., Conti M. Absence of muscarinic cholinergic airway responses in mice deficient in the cyclic nucleotide phosphodiesterase PDE4D. Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6751–6756. doi: 10.1073/pnas.97.12.6751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Herman S. B., Juilfs D. M., Fauman E. B., Juneau P., Menetski J. P. Analysis of a mutation in phosphodiesterase type 4 that alters both inhibitor activity and nucleotide selectivity. Mol Pharmacol. 2000 May;57(5):991–999. [PubMed] [Google Scholar]
  39. Hoffmann R., Baillie G. S., MacKenzie S. J., Yarwood S. J., Houslay M. D. The MAP kinase ERK2 inhibits the cyclic AMP-specific phosphodiesterase HSPDE4D3 by phosphorylating it at Ser579. EMBO J. 1999 Feb 15;18(4):893–903. doi: 10.1093/emboj/18.4.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Hoffmann R., Wilkinson I. R., McCallum J. F., Engels P., Houslay M. D. cAMP-specific phosphodiesterase HSPDE4D3 mutants which mimic activation and changes in rolipram inhibition triggered by protein kinase A phosphorylation of Ser-54: generation of a molecular model. Biochem J. 1998 Jul 1;333(Pt 1):139–149. doi: 10.1042/bj3330139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Horton Y. M., Sullivan M., Houslay M. D. 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]. Biochem J. 1995 Jun 1;308(Pt 2):683–691. doi: 10.1042/bj3080683. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Houslay M. D., Kolch W. Cell-type specific integration of cross-talk between extracellular signal-regulated kinase and cAMP signaling. Mol Pharmacol. 2000 Oct;58(4):659–668. [PubMed] [Google Scholar]
  43. Houslay M. D., Milligan G. Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci. 1997 Jun;22(6):217–224. doi: 10.1016/s0968-0004(97)01050-5. [DOI] [PubMed] [Google Scholar]
  44. Houslay M. D. PDE4 cAMP-specific phosphodiesterases. Prog Nucleic Acid Res Mol Biol. 2001;69:249–315. doi: 10.1016/s0079-6603(01)69049-4. [DOI] [PubMed] [Google Scholar]
  45. Houslay M. D., Sullivan M., Bolger G. B. The multienzyme PDE4 cyclic adenosine monophosphate-specific phosphodiesterase family: intracellular targeting, regulation, and selective inhibition by compounds exerting anti-inflammatory and antidepressant actions. Adv Pharmacol. 1998;44:225–342. doi: 10.1016/s1054-3589(08)60128-3. [DOI] [PubMed] [Google Scholar]
  46. Huang Z., Ducharme Y., Macdonald D., Robichaud A. The next generation of PDE4 inhibitors. Curr Opin Chem Biol. 2001 Aug;5(4):432–438. doi: 10.1016/s1367-5931(00)00224-6. [DOI] [PubMed] [Google Scholar]
  47. Hurley J. H., Meyer T. Subcellular targeting by membrane lipids. Curr Opin Cell Biol. 2001 Apr;13(2):146–152. doi: 10.1016/s0955-0674(00)00191-5. [DOI] [PubMed] [Google Scholar]
  48. Hurley J. H., Misra S. Signaling and subcellular targeting by membrane-binding domains. Annu Rev Biophys Biomol Struct. 2000;29:49–79. doi: 10.1146/annurev.biophys.29.1.49. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Huston E., Beard M., McCallum F., Pyne N. J., Vandenabeele P., Scotland G., Houslay M. D. The cAMP-specific phosphodiesterase PDE4A5 is cleaved downstream of its SH3 interaction domain by caspase-3. Consequences for altered intracellular distribution. J Biol Chem. 2000 Sep 8;275(36):28063–28074. doi: 10.1074/jbc.M906144199. [DOI] [PubMed] [Google Scholar]
  50. Huston E., Lumb S., Russell A., Catterall C., Ross A. H., Steele M. R., Bolger G. B., Perry M. J., Owens R. J., Houslay M. D. Molecular cloning and transient expression in COS7 cells of a novel human PDE4B cAMP-specific phosphodiesterase, HSPDE4B3. Biochem J. 1997 Dec 1;328(Pt 2):549–558. doi: 10.1042/bj3280549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Jacobitz S., McLaughlin M. M., Livi G. P., Burman M., Torphy T. J. Mapping the functional domains of human recombinant phosphodiesterase 4A: structural requirements for catalytic activity and rolipram binding. Mol Pharmacol. 1996 Oct;50(4):891–899. [PubMed] [Google Scholar]
  52. Jin S-L Catherine, Conti Marco. Induction of the cyclic nucleotide phosphodiesterase PDE4B is essential for LPS-activated TNF-alpha responses. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7628–7633. doi: 10.1073/pnas.122041599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Jin S. L., Swinnen J. V., Conti M. Characterization of the structure of a low Km, rolipram-sensitive cAMP phosphodiesterase. Mapping of the catalytic domain. J Biol Chem. 1992 Sep 15;267(26):18929–18939. [PubMed] [Google Scholar]
  54. Jurevicius J., Fischmeister R. cAMP compartmentation is responsible for a local activation of cardiac Ca2+ channels by beta-adrenergic agonists. Proc Natl Acad Sci U S A. 1996 Jan 9;93(1):295–299. doi: 10.1073/pnas.93.1.295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Kawasaki H., Springett G. M., Mochizuki N., Toki S., Nakaya M., Matsuda M., Housman D. E., Graybiel A. M. A family of cAMP-binding proteins that directly activate Rap1. Science. 1998 Dec 18;282(5397):2275–2279. doi: 10.1126/science.282.5397.2275. [DOI] [PubMed] [Google Scholar]
  56. Kovala T., Sanwal B. D., Ball E. H. Recombinant expression of a type IV, cAMP-specific phosphodiesterase: characterization and structure-function studies of deletion mutants. Biochemistry. 1997 Mar 11;36(10):2968–2976. doi: 10.1021/bi9613483. [DOI] [PubMed] [Google Scholar]
  57. Laliberté F., Han Y., Govindarajan A., Giroux A., Liu S., Bobechko B., Lario P., Bartlett A., Gorseth E., Gresser M. Conformational difference between PDE4 apoenzyme and holoenzyme. Biochemistry. 2000 May 30;39(21):6449–6458. doi: 10.1021/bi992432w. [DOI] [PubMed] [Google Scholar]
  58. Laliberté France, Liu Susana, Gorseth Elise, Bobechko Brian, Bartlett Adrienne, Lario Paula, Gresser Michael J., Huang Zheng. In vitro PKA phosphorylation-mediated human PDE4A4 activation. FEBS Lett. 2002 Feb 13;512(1-3):205–208. doi: 10.1016/s0014-5793(02)02259-7. [DOI] [PubMed] [Google Scholar]
  59. Le Jeune Ivan R., Shepherd Malcolm, Van Heeke Gino, Houslay Miles D., Hall Ian P. Cyclic AMP-dependent transcriptional up-regulation of phosphodiesterase 4D5 in human airway smooth muscle cells. Identification and characterization of a novel PDE4D5 promoter. J Biol Chem. 2002 Jul 16;277(39):35980–35989. doi: 10.1074/jbc.M204832200. [DOI] [PubMed] [Google Scholar]
  60. Lee Mi Eun, Markowitz Joseph, Lee Jie Oh, Lee Hayyoung. Crystal structure of phosphodiesterase 4D and inhibitor complex(1). FEBS Lett. 2002 Oct 23;530(1-3):53–58. doi: 10.1016/s0014-5793(02)03396-3. [DOI] [PubMed] [Google Scholar]
  61. Lim J., Pahlke G., Conti M. Activation of the cAMP-specific phosphodiesterase PDE4D3 by phosphorylation. Identification and function of an inhibitory domain. J Biol Chem. 1999 Jul 9;274(28):19677–19685. doi: 10.1074/jbc.274.28.19677. [DOI] [PubMed] [Google Scholar]
  62. Liu H., Maurice D. H. Phosphorylation-mediated activation and translocation of the cyclic AMP-specific phosphodiesterase PDE4D3 by cyclic AMP-dependent protein kinase and mitogen-activated protein kinases. A potential mechanism allowing for the coordinated regulation of PDE4D activity and targeting. J Biol Chem. 1999 Apr 9;274(15):10557–10565. doi: 10.1074/jbc.274.15.10557. [DOI] [PubMed] [Google Scholar]
  63. Liu S., Laliberté F., Bobechko B., Bartlett A., Lario P., Gorseth E., Van Hamme J., Gresser M. J., Huang Z. Dissecting the cofactor-dependent and independent bindings of PDE4 inhibitors. Biochemistry. 2001 Aug 28;40(34):10179–10186. doi: 10.1021/bi010096p. [DOI] [PubMed] [Google Scholar]
  64. Londesborough J. Evidence that the peripheral cyclic AMP phosphodiesterase of rat liver plasma membranes is a metalloenzyme. Biochem J. 1985 Jan 1;225(1):143–147. doi: 10.1042/bj2250143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Luttrell Louis M., Lefkowitz Robert J. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J Cell Sci. 2002 Feb 1;115(Pt 3):455–465. doi: 10.1242/jcs.115.3.455. [DOI] [PubMed] [Google Scholar]
  66. MacKenzie S. J., Baillie G. S., McPhee I., Bolger G. B., Houslay M. D. 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. J Biol Chem. 2000 Jun 2;275(22):16609–16617. doi: 10.1074/jbc.275.22.16609. [DOI] [PubMed] [Google Scholar]
  67. MacKenzie S. J., Houslay M. D. 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. Biochem J. 2000 Apr 15;347(Pt 2):571–578. doi: 10.1042/0264-6021:3470571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. MacKenzie S. J., Yarwood S. J., Peden A. H., Bolger G. B., Vernon R. G., Houslay M. D. Stimulation of p70S6 kinase via a growth hormone-controlled phosphatidylinositol 3-kinase pathway leads to the activation of a PDE4A cyclic AMP-specific phosphodiesterase in 3T3-F442A preadipocytes. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3549–3554. doi: 10.1073/pnas.95.7.3549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  69. MacKenzie Simon J., Baillie George S., McPhee Ian, MacKenzie Carolynn, Seamons Rachael, McSorley Theresa, Millen Jenni, Beard Matthew B., van Heeke Gino, Houslay Miles D. Long PDE4 cAMP specific phosphodiesterases are activated by protein kinase A-mediated phosphorylation of a single serine residue in Upstream Conserved Region 1 (UCR1). Br J Pharmacol. 2002 Jun;136(3):421–433. doi: 10.1038/sj.bjp.0704743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Manganiello V. C., Degerman E. Cyclic nucleotide phosphodiesterases (PDEs): diverse regulators of cyclic nucleotide signals and inviting molecular targets for novel therapeutic agents. Thromb Haemost. 1999 Aug;82(2):407–411. [PubMed] [Google Scholar]
  71. Marchmont R. J., Houslay M. D. A peripheral and an intrinsic enzyme constitute the cyclic AMP phosphodiesterase activity of rat liver plasma membranes. Biochem J. 1980 May 1;187(2):381–392. doi: 10.1042/bj1870381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Marcoz P., Némoz G., Prigent A. F., Lagarde M. Phosphatidic acid stimulates the rolipram-sensitive cyclic nucleotide phosphodiesterase from rat thymocytes. Biochim Biophys Acta. 1993 Mar 10;1176(1-2):129–136. doi: 10.1016/0167-4889(93)90187-t. [DOI] [PubMed] [Google Scholar]
  73. McCahill Angela, Warwicker Jim, Bolger Graeme B., Houslay Miles D., Yarwood Stephen J. The RACK1 scaffold protein: a dynamic cog in cell response mechanisms. Mol Pharmacol. 2002 Dec;62(6):1261–1273. doi: 10.1124/mol.62.6.1261. [DOI] [PubMed] [Google Scholar]
  74. McPhee I., Pooley L., Lobban M., Bolger G., Houslay M. D. Identification, characterization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem J. 1995 Sep 15;310(Pt 3):965–974. doi: 10.1042/bj3100965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. McPhee I., Yarwood S. J., Scotland G., Huston E., Beard M. B., Ross A. H., Houslay E. S., Houslay M. D. 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. J Biol Chem. 1999 Apr 23;274(17):11796–11810. doi: 10.1074/jbc.274.17.11796. [DOI] [PubMed] [Google Scholar]
  76. Murthy Karnam S., Zhou Huiping, Makhlouf Gabriel M. PKA-dependent activation of PDE3A and PDE4 and inhibition of adenylyl cyclase V/VI in smooth muscle. Am J Physiol Cell Physiol. 2002 Mar;282(3):C508–C517. doi: 10.1152/ajpcell.00373.2001. [DOI] [PubMed] [Google Scholar]
  77. Newlon M. G., Roy M., Morikis D., Hausken Z. E., Coghlan V., Scott J. D., Jennings P. A. The molecular basis for protein kinase A anchoring revealed by solution NMR. Nat Struct Biol. 1999 Mar;6(3):222–227. doi: 10.1038/6663. [DOI] [PubMed] [Google Scholar]
  78. Némoz G., Sette C., Conti M. Selective activation of rolipram-sensitive, cAMP-specific phosphodiesterase isoforms by phosphatidic acid. Mol Pharmacol. 1997 Feb;51(2):242–249. doi: 10.1124/mol.51.2.242. [DOI] [PubMed] [Google Scholar]
  79. O'Connell J. C., McCallum J. F., McPhee I., Wakefield J., Houslay E. S., Wishart W., Bolger G., Frame M., Houslay M. D. The SH3 domain of Src tyrosyl protein kinase interacts with the N-terminal splice region of the PDE4A cAMP-specific phosphodiesterase RPDE-6 (RNPDE4A5). Biochem J. 1996 Aug 15;318(Pt 1):255–261. doi: 10.1042/bj3180255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. O'Donnell J. M. Antidepressant-like effects of rolipram and other inhibitors of cyclic adenosine monophosphate phosphodiesterase on behavior maintained by differential reinforcement of low response rate. J Pharmacol Exp Ther. 1993 Mar;264(3):1168–1178. [PubMed] [Google Scholar]
  81. Oki N., Takahashi S. I., Hidaka H., Conti M. Short term feedback regulation of cAMP in FRTL-5 thyroid cells. Role of PDE4D3 phosphodiesterase activation. J Biol Chem. 2000 Apr 14;275(15):10831–10837. doi: 10.1074/jbc.275.15.10831. [DOI] [PubMed] [Google Scholar]
  82. Owens R. J., Catterall C., Batty D., Jappy J., Russell A., Smith B., O'Connell J., Perry M. J. Human phosphodiesterase 4A: characterization of full-length and truncated enzymes expressed in COS cells. Biochem J. 1997 Aug 15;326(Pt 1):53–60. doi: 10.1042/bj3260053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Pawson T. Protein modules and signalling networks. Nature. 1995 Feb 16;373(6515):573–580. doi: 10.1038/373573a0. [DOI] [PubMed] [Google Scholar]
  84. Perry Stephen J., Baillie George S., Kohout Trudy A., McPhee Ian, Magiera Maria M., Ang Kok Long, Miller William E., McLean Alison J., Conti Marco, Houslay Miles D. Targeting of cyclic AMP degradation to beta 2-adrenergic receptors by beta-arrestins. Science. 2002 Oct 25;298(5594):834–836. doi: 10.1126/science.1074683. [DOI] [PubMed] [Google Scholar]
  85. Qiu Y. H., Chen C. N., Malone T., Richter L., Beckendorf S. K., Davis R. L. Characterization of the memory gene dunce of Drosophila melanogaster. J Mol Biol. 1991 Dec 5;222(3):553–565. doi: 10.1016/0022-2836(91)90496-s. [DOI] [PubMed] [Google Scholar]
  86. Reeves M. L., Leigh B. K., England P. J. The identification of a new cyclic nucleotide phosphodiesterase activity in human and guinea-pig cardiac ventricle. Implications for the mechanism of action of selective phosphodiesterase inhibitors. Biochem J. 1987 Jan 15;241(2):535–541. doi: 10.1042/bj2410535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Rena G., Begg F., Ross A., MacKenzie C., McPhee I., Campbell L., Huston E., Sullivan M., Houslay M. D. Molecular cloning, genomic positioning, promoter identification, and characterization of the novel cyclic amp-specific phosphodiesterase PDE4A10. Mol Pharmacol. 2001 May;59(5):996–1011. doi: 10.1124/mol.59.5.996. [DOI] [PubMed] [Google Scholar]
  88. Rich T. C., Fagan K. A., Tse T. E., Schaack J., Cooper D. M., Karpen J. W. A uniform extracellular stimulus triggers distinct cAMP signals in different compartments of a simple cell. Proc Natl Acad Sci U S A. 2001 Oct 16;98(23):13049–13054. doi: 10.1073/pnas.221381398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Rich T. C., Tse T. E., Rohan J. G., Schaack J., Karpen J. W. In vivo assessment of local phosphodiesterase activity using tailored cyclic nucleotide-gated channels as cAMP sensors. J Gen Physiol. 2001 Jul;118(1):63–78. doi: 10.1085/jgp.118.1.63. [DOI] [PMC free article] [PubMed] [Google Scholar]
  90. Richter W., Unciuleac L., Hermsdorf T., Kronbach T., Dettmer D. Identification of inhibitor binding sites of the cAMP-specific phosphodiesterase 4. Cell Signal. 2001 Apr;13(4):287–297. doi: 10.1016/s0898-6568(01)00150-4. [DOI] [PubMed] [Google Scholar]
  91. Richter W., Unciuleac L., Hermsdorf T., Kronbach T., Dettmer D. Identification of substrate specificity determinants in human cAMP-specific phosphodiesterase 4A by single-point mutagenesis. Cell Signal. 2001 Mar;13(3):159–167. doi: 10.1016/s0898-6568(01)00142-5. [DOI] [PubMed] [Google Scholar]
  92. Richter Wito, Conti Marco. Dimerization of the type 4 cAMP-specific phosphodiesterases is mediated by the upstream conserved regions (UCRs). J Biol Chem. 2002 Aug 12;277(43):40212–40221. doi: 10.1074/jbc.M203585200. [DOI] [PubMed] [Google Scholar]
  93. Rocque W. J., Holmes W. D., Patel I. R., Dougherty R. W., Ittoop O., Overton L., Hoffman C. R., Wisely G. B., Willard D. H., Luther M. A. Detailed characterization of a purified type 4 phosphodiesterase, HSPDE4B2B: differentiation of high- and low-affinity (R)-rolipram binding. Protein Expr Purif. 1997 Mar;9(2):191–202. doi: 10.1006/prep.1996.0683. [DOI] [PubMed] [Google Scholar]
  94. Rocque W. J., Tian G., Wiseman J. S., Holmes W. D., Zajac-Thompson I., Willard D. H., Patel I. R., Wisely G. B., Clay W. C., Kadwell S. H. Human recombinant phosphodiesterase 4B2B binds (R)-rolipram at a single site with two affinities. Biochemistry. 1997 Nov 18;36(46):14250–14261. doi: 10.1021/bi971112e. [DOI] [PubMed] [Google Scholar]
  95. Ron D., Chen C. H., Caldwell J., Jamieson L., Orr E., Mochly-Rosen D. Cloning of an intracellular receptor for protein kinase C: a homolog of the beta subunit of G proteins. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):839–843. doi: 10.1073/pnas.91.3.839. [DOI] [PMC free article] [PubMed] [Google Scholar]
  96. Rubin C. S. A kinase anchor proteins and the intracellular targeting of signals carried by cyclic AMP. Biochim Biophys Acta. 1994 Dec 30;1224(3):467–479. [PubMed] [Google Scholar]
  97. Savany A., Abriat C., Némoz G., Lagarde M., Prigent A. F. Activation of a cyclic nucleotide phosphodiesterase 4 (PDE4) from rat thymocytes by phosphatidic acid. Cell Signal. 1996 Nov;8(7):511–516. doi: 10.1016/s0898-6568(96)00107-6. [DOI] [PubMed] [Google Scholar]
  98. Schmidt D., Dent G., Rabe K. F. Selective phosphodiesterase inhibitors for the treatment of bronchial asthma and chronic obstructive pulmonary disease. Clin Exp Allergy. 1999 Jun;29 (Suppl 2):99–109. doi: 10.1046/j.1365-2222.1999.00018.x. [DOI] [PubMed] [Google Scholar]
  99. Scotland G., Houslay M. D. Chimeric constructs show that the unique N-terminal domain of the cyclic AMP phosphodiesterase RD1 (RNPDE4A1A; rPDE-IVA1) can confer membrane association upon the normally cytosolic protein chloramphenicol acetyltransferase. Biochem J. 1995 Jun 1;308(Pt 2):673–681. doi: 10.1042/bj3080673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  100. Sette C., Conti M. Phosphorylation and activation of a cAMP-specific phosphodiesterase by the cAMP-dependent protein kinase. Involvement of serine 54 in the enzyme activation. J Biol Chem. 1996 Jul 12;271(28):16526–16534. doi: 10.1074/jbc.271.28.16526. [DOI] [PubMed] [Google Scholar]
  101. Sette C., Iona S., Conti M. The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. J Biol Chem. 1994 Mar 25;269(12):9245–9252. [PubMed] [Google Scholar]
  102. Sette C., Vicini E., Conti M. Modulation of cellular responses by hormones: role of cAMP specific, rolipram-sensitive phosphodiesterases. Mol Cell Endocrinol. 1994 Apr;100(1-2):75–79. doi: 10.1016/0303-7207(94)90282-8. [DOI] [PubMed] [Google Scholar]
  103. Sette C., Vicini E., Conti M. The ratPDE3/IVd phosphodiesterase gene codes for multiple proteins differentially activated by cAMP-dependent protein kinase. J Biol Chem. 1994 Jul 15;269(28):18271–18274. [PubMed] [Google Scholar]
  104. Shakur Y., Pryde J. G., Houslay M. D. Engineered deletion of the unique N-terminal domain of the cyclic AMP-specific phosphodiesterase RD1 prevents plasma membrane association and the attainment of enhanced thermostability without altering its sensitivity to inhibition by rolipram. Biochem J. 1993 Jun 15;292(Pt 3):677–686. doi: 10.1042/bj2920677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Shakur Y., Wilson M., Pooley L., Lobban M., Griffiths S. L., Campbell A. M., Beattie J., Daly C., Houslay M. D. Identification and characterization of the type-IVA cyclic AMP-specific phosphodiesterase RD1 as a membrane-bound protein expressed in cerebellum. Biochem J. 1995 Mar 15;306(Pt 3):801–809. doi: 10.1042/bj3060801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  106. Sharrocks A. D., Yang S. H., Galanis A. Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem Sci. 2000 Sep;25(9):448–453. doi: 10.1016/s0968-0004(00)01627-3. [DOI] [PubMed] [Google Scholar]
  107. Smith K. J., Scotland G., Beattie J., Trayer I. P., Houslay M. D. Determination of the structure of the N-terminal splice region of the cyclic AMP-specific phosphodiesterase RD1 (RNPDE4A1) by 1H NMR and identification of the membrane association domain using chimeric constructs. J Biol Chem. 1996 Jul 12;271(28):16703–16711. doi: 10.1074/jbc.271.28.16703. [DOI] [PubMed] [Google Scholar]
  108. Soderling S. H., Beavo J. A. Regulation of cAMP and cGMP signaling: new phosphodiesterases and new functions. Curr Opin Cell Biol. 2000 Apr;12(2):174–179. doi: 10.1016/s0955-0674(99)00073-3. [DOI] [PubMed] [Google Scholar]
  109. Souness J. E., Rao S. Proposal for pharmacologically distinct conformers of PDE4 cyclic AMP phosphodiesterases. Cell Signal. 1997 May-Jun;9(3-4):227–236. doi: 10.1016/s0898-6568(96)00173-8. [DOI] [PubMed] [Google Scholar]
  110. Spina D., Landells L. J., Page C. P. The role of phosphodiesterase enzymes in allergy and asthma. Adv Pharmacol. 1998;44:33–89. doi: 10.1016/s1054-3589(08)60125-8. [DOI] [PubMed] [Google Scholar]
  111. Steele M. R., McCahill A., Thompson D. S., MacKenzie C., Isaacs N. W., Houslay M. D., Bolger G. B. Identification of a surface on the beta-propeller protein RACK1 that interacts with the cAMP-specific phosphodiesterase PDE4D5. Cell Signal. 2001 Jul;13(7):507–513. doi: 10.1016/s0898-6568(01)00167-x. [DOI] [PubMed] [Google Scholar]
  112. Sullivan M., Olsen A. S., Houslay M. D. Genomic organisation of the human cyclic AMP-specific phosphodiesterase PDE4C gene and its chromosomal localisation to 19p13.1, between RAB3A and JUND. Cell Signal. 1999 Oct;11(10):735–742. doi: 10.1016/s0898-6568(99)00037-6. [DOI] [PubMed] [Google Scholar]
  113. Sullivan M., Rena G., Begg F., Gordon L., Olsen A. S., Houslay M. D. 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. Biochem J. 1998 Aug 1;333(Pt 3):693–703. doi: 10.1042/bj3330693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  114. Swinnen J. V., Joseph D. R., Conti M. Molecular cloning of rat homologues of the Drosophila melanogaster dunce cAMP phosphodiesterase: evidence for a family of genes. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5325–5329. doi: 10.1073/pnas.86.14.5325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Taskén K. A., Collas P., Kemmner W. A., Witczak O., Conti M., Taskén K. Phosphodiesterase 4D and protein kinase a type II constitute a signaling unit in the centrosomal area. J Biol Chem. 2001 Apr 2;276(25):21999–22002. doi: 10.1074/jbc.C000911200. [DOI] [PubMed] [Google Scholar]
  116. Torphy T. J. Phosphodiesterase isozymes: molecular targets for novel antiasthma agents. Am J Respir Crit Care Med. 1998 Feb;157(2):351–370. doi: 10.1164/ajrccm.157.2.9708012. [DOI] [PubMed] [Google Scholar]
  117. Verde I., Pahlke G., Salanova M., Zhang G., Wang S., Coletti D., Onuffer J., Jin S. L., Conti M. Myomegalin is a novel protein of the golgi/centrosome that interacts with a cyclic nucleotide phosphodiesterase. J Biol Chem. 2000 Dec 27;276(14):11189–11198. doi: 10.1074/jbc.M006546200. [DOI] [PubMed] [Google Scholar]
  118. Vicini E., Conti M. Characterization of an intronic promoter of a cyclic adenosine 3',5'-monophosphate (cAMP)-specific phosphodiesterase gene that confers hormone and cAMP inducibility. Mol Endocrinol. 1997 Jun;11(7):839–850. doi: 10.1210/mend.11.7.9941. [DOI] [PubMed] [Google Scholar]
  119. Wachtel H. Characteristic behavioural alterations in rats induced by rolipram and other selective adenosine cyclic 3', 5'-monophosphate phosphodiesterase inhibitors. Psychopharmacology (Berl) 1982;77(4):309–316. doi: 10.1007/BF00432761. [DOI] [PubMed] [Google Scholar]
  120. Xu R. X., Hassell A. M., Vanderwall D., Lambert M. H., Holmes W. D., Luther M. A., Rocque W. J., Milburn M. V., Zhao Y., Ke H. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822–1825. doi: 10.1126/science.288.5472.1822. [DOI] [PubMed] [Google Scholar]
  121. Yarwood S. J., Steele M. R., Scotland G., Houslay M. D., Bolger G. B. The RACK1 signaling scaffold protein selectively interacts with the cAMP-specific phosphodiesterase PDE4D5 isoform. J Biol Chem. 1999 May 21;274(21):14909–14917. doi: 10.1074/jbc.274.21.14909. [DOI] [PubMed] [Google Scholar]
  122. Zaccolo Manuela, Pozzan Tullio. Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science. 2002 Mar 1;295(5560):1711–1715. doi: 10.1126/science.1069982. [DOI] [PubMed] [Google Scholar]
  123. Zhan C. G., Zheng F. First computational evidence for a catalytic bridging hydroxide ion in a phosphodiesterase active site. J Am Chem Soc. 2001 Mar 28;123(12):2835–2838. doi: 10.1021/ja005529a. [DOI] [PubMed] [Google Scholar]
  124. Zhang H. T., Crissman A. M., Dorairaj N. R., Chandler L. J., O'Donnell J. M. Inhibition of cyclic AMP phosphodiesterase (PDE4) reverses memory deficits associated with NMDA receptor antagonism. Neuropsychopharmacology. 2000 Aug;23(2):198–204. doi: 10.1016/S0893-133X(00)00108-1. [DOI] [PubMed] [Google Scholar]
  125. Zhang H. T., O'Donnell J. M. Effects of rolipram on scopolamine-induced impairment of working and reference memory in the radial-arm maze tests in rats. Psychopharmacology (Berl) 2000 Jun;150(3):311–316. doi: 10.1007/s002130000414. [DOI] [PubMed] [Google Scholar]
  126. Zhang J., Ma Y., Taylor S. S., Tsien R. Y. Genetically encoded reporters of protein kinase A activity reveal impact of substrate tethering. Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):14997–15002. doi: 10.1073/pnas.211566798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. de Rooij J., Zwartkruis F. J., Verheijen M. H., Cool R. H., Nijman S. M., Wittinghofer A., Bos J. L. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature. 1998 Dec 3;396(6710):474–477. doi: 10.1038/24884. [DOI] [PubMed] [Google Scholar]

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