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Gene Review

PDE3A  -  phosphodiesterase 3A, cGMP-inhibited

Homo sapiens

Synonyms: CGI-PDE, CGI-PDE A, CGI-PDE-A, Cyclic GMP-inhibited phosphodiesterase A, cGMP-inhibited 3',5'-cyclic phosphodiesterase A
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Disease relevance of PDE3A

  • This may be mediated via a protein kinase A-dependent mechanism, as treatment of cells with Br-cAMP (100 microM) mimicked chronic hypoxia in increasing PDE3A expression, while the PKA inhibitor, H8 peptide (50 microM) abolished the hypoxic-dependent increase in PDE3A transcript [1].
  • To obtain structural information on platelet PDE3A, we cloned the enzyme cDNA from a human erythroleukemia cell (HEL) library since the cell line expresses many platelet proteins [2].
  • A functional truncated recombinant PDE3A containing the catalytic domain (PDE3Atriangle up1) and mutant proteins were expressed in a baculovirus/Sf9 cell system [3].
  • The differences in PDE3A expression and responses may be the result of hypertension rather than the cause [4].

Psychiatry related information on PDE3A

  • The data obtained indicate that neither the expression levels nor the sequence deviations of PDE3A are the main reasons for erectile dysfunction in men [5].

High impact information on PDE3A

  • We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity [6].
  • cGMP-inhibited cAMP phosphodiesterase 3A (PDE3A) is expressed in mouse oocytes, and its function is indispensable for meiotic maturation as demonstrated by genetic ablation [7].
  • Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation [7].
  • This effect is greatly decreased by mutation of any of the PDE3A serines 290-292 to alanine in both Xenopus and mouse [7].
  • Here, we demonstrate that ICER induction repressed PDE3A gene transcription [8].

Biological context of PDE3A

  • Of the 11 human PDEs, only PDE3A and 3B have 44-amino acid inserts in the catalytic domain [9].
  • 5. RT - PCR using specific primers for PDE3B, but not for PDE3A, amplified, from BRIN - BD11 cell total RNA, a 351 base pair product that was >97% homologous with rat adipose tissue PDE3B [10].
  • The most distal transcription initiation site of the PDE3A gene is approximately 1071 bases upstream of the ATG site, suggesting that exon 1 consists of 1071 and 960 bp of untranslated and translated sequences, respectively [11].
  • Here, we describe PDE3A gene structure, which comprises 16 exons spanning over 130 kb on chromosome 12p12 [11].
  • We have cloned the coding region of a human gene, whose predicted amino acid sequence shows 88% homology and higher correspondence in functional domains to the rat cGMP inhibited phosphodiesterase gene (PDE3A) [12].

Anatomical context of PDE3A


Associations of PDE3A with chemical compounds


Physical interactions of PDE3A

  • An additional observation was that the cytoskeletal cross-linker protein plectin-1 coimmunoprecipitated with PDE3A independently of 14-3-3 binding [16].

Other interactions of PDE3A

  • Platelets contain two cAMP phosphodiesterases (PDEs) which regulate intracellular cAMP levels, cGMP-inhibited cAMP PDE (PDE3A) and cGMP-stimulated PDE (PDE2A) [19].
  • As revealed by reverse transcriptase polymerase chain reaction, of all tissues of the urogenital tract analyzed the expression of the PDE3A gene was highest in the corpus cavernosum [5].
  • Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop [8].
  • These findings are compatible with elevation of cGMP by NO in a compartment close to PDE3A, PKA, and VASP, leading to a local increase of cAMP able to block thrombin-induced shape change [20].
  • To identify amino acid residues involved in PDE3-selective inhibitor binding, we selected eight presumed interacting residues in the substrate-binding pocket of PDE3A using a model created on basis of homology to the PDE4B crystal structure [21].

Analytical, diagnostic and therapeutic context of PDE3A


  1. Increased expression of the cGMP-inhibited cAMP-specific (PDE3) and cGMP binding cGMP-specific (PDE5) phosphodiesterases in models of pulmonary hypertension. Murray, F., MacLean, M.R., Pyne, N.J. Br. J. Pharmacol. (2002) [Pubmed]
  2. Human platelet cGI-PDE: expression in yeast and localization of the catalytic domain by deletion mutagenesis. Cheung, P.P., Xu, H., McLaughlin, M.M., Ghazaleh, F.A., Livi, G.P., Colman, R.W. Blood (1996) [Pubmed]
  3. Conserved amino acids in metal-binding motifs of PDE3A are involved in substrate and inhibitor binding. Zhang, W., Colman, R.W. Blood (2000) [Pubmed]
  4. Autosomal-dominant hypertension with type E brachydactyly is caused by rearrangement on the short arm of chromosome 12. Bähring, S., Rauch, A., Toka, O., Schroeder, C., Hesse, C., Siedler, H., Fesüs, G., Haefeli, W.E., Busjahn, A., Aydin, A., Neuenfeld, Y., Mühl, A., Toka, H.R., Gollasch, M., Jordan, J., Luft, F.C. Hypertension (2004) [Pubmed]
  5. Molecular biological characterization of phosphodiesterase 3A from human corpus cavernosum. Küthe, A., Eckel, H., Stief, C.G., Uckert, S., Forssmann, W.G., Jonas, U., Mägert, H.J. Chem. Biol. Interact. (1999) [Pubmed]
  6. Cyclic nucleotide phosphodiesterase 3A-deficient mice as a model of female infertility. Masciarelli, S., Horner, K., Liu, C., Park, S.H., Hinckley, M., Hockman, S., Nedachi, T., Jin, C., Conti, M., Manganiello, V. J. Clin. Invest. (2004) [Pubmed]
  7. Protein kinase B/Akt phosphorylation of PDE3A and its role in mammalian oocyte maturation. Han, S.J., Vaccari, S., Nedachi, T., Andersen, C.B., Kovacina, K.S., Roth, R.A., Conti, M. EMBO J. (2006) [Pubmed]
  8. A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis. Ding, B., Abe, J., Wei, H., Xu, H., Che, W., Aizawa, T., Liu, W., Molina, C.A., Sadoshima, J., Blaxall, B.C., Berk, B.C., Yan, C. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  9. New Insights from the Structure-Function Analysis of the Catalytic Region of Human Platelet Phosphodiesterase 3A: A ROLE FOR THE UNIQUE 44-AMINO ACID INSERT. Hung, S.H., Zhang, W., Pixley, R.A., Jameson, B.A., Huang, Y.C., Colman, R.F., Colman, R.W. J. Biol. Chem. (2006) [Pubmed]
  10. Effect of type-selective inhibitors on cyclic nucleotide phosphodiesterase activity and insulin secretion in the clonal insulin secreting cell line BRIN-BD11. Ahmad, M., Abdel-Wahab, Y.H., Tate, R., Flatt, P.R., Pyne, N.J., Furman, B.L. Br. J. Pharmacol. (2000) [Pubmed]
  11. Cardiac type cGMP-inhibited phosphodiesterase (PDE3A) gene structure: similarity and difference to adipocyte type PDE3B gene. Kasuya, J., Liang, S.J., Goko, H., Park, S.H., Kato, K., Xu, Z.D., Hockman, S., Manganiello, V.C., Fujita-Yamaguchi, Y. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  12. Molecular cloning and chromosomal assignment of the human homologue of the rat cGMP-inhibited phosphodiesterase 1 (PDE3A)--a gene involved in fat metabolism located at 11p 15.1. Löbbert, R.W., Winterpacht, A., Seipel, B., Zabel, B.U. Genomics (1996) [Pubmed]
  13. Phenotype-based screening of mechanistically annotated compounds in combination with gene expression and pathway analysis identifies candidate drug targets in a human squamous carcinoma cell model. Fryknäs, M., Rickardson, L., Wickström, M., Dhar, S., Lövborg, H., Gullbo, J., Nygren, P., Gustafsson, M.G., Isaksson, A., Larsson, R. Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening. (2006) [Pubmed]
  14. Isoforms of cyclic nucleotide phosphodiesterase PDE3A in cardiac myocytes. Wechsler, J., Choi, Y.H., Krall, J., Ahmad, F., Manganiello, V.C., Movsesian, M.A. J. Biol. Chem. (2002) [Pubmed]
  15. Presence of cyclic nucleotide phosphodiesterases PDE1A, existing as a stable complex with calmodulin, and PDE3A in human spermatozoa. Lefièvre, L., de Lamirande, E., Gagnon, C. Biol. Reprod. (2002) [Pubmed]
  16. Phosphodiesterase 3A binds to 14-3-3 proteins in response to PMA-induced phosphorylation of Ser428. Pozuelo Rubio, M., Campbell, D.G., Morrice, N.A., Mackintosh, C. Biochem. J. (2005) [Pubmed]
  17. Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels. Sim, D.S., Merrill-Skoloff, G., Furie, B.C., Furie, B., Flaumenhaft, R. Blood (2004) [Pubmed]
  18. Protein kinase C-mediated phosphorylation and activation of PDE3A regulate cAMP levels in human platelets. Hunter, R.W., Mackintosh, C., Hers, I. J. Biol. Chem. (2009) [Pubmed]
  19. Differential regulation of human platelet responses by cGMP inhibited and stimulated cAMP phosphodiesterases. Manns, J.M., Brenna, K.J., Colman, R.W., Sheth, S.B. Thromb. Haemost. (2002) [Pubmed]
  20. Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide. Jensen, B.O., Selheim, F., Døskeland, S.O., Gear, A.R., Holmsen, H. Blood (2004) [Pubmed]
  21. Identification of interaction sites of cyclic nucleotide phosphodiesterase type 3A with milrinone and cilostazol using molecular modeling and site-directed mutagenesis. Zhang, W., Ke, H., Colman, R.W. Mol. Pharmacol. (2002) [Pubmed]
  22. Cyclic AMP phosphodiesterases in human lymphocytes. Sheth, S.B., Chaganti, K., Bastepe, M., Ajuria, J., Brennan, K., Biradavolu, R., Colman, R.W. Br. J. Haematol. (1997) [Pubmed]
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