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Gene Review

PDE5A  -  phosphodiesterase 5A, cGMP-specific

Homo sapiens

Synonyms: CGB-PDE, CN5A, PDE5, cGMP-binding cGMP-specific phosphodiesterase, cGMP-specific 3',5'-cyclic phosphodiesterase
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Disease relevance of PDE5A


Psychiatry related information on PDE5A

  • Furthermore, indications of side effects of specific inhibitors in certain tissues as well as of a possible relation between the level of PDE3A and PDE5A gene expression and erectile dysfunction should have been deduced from the results obtained [6].
  • The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus maze task [7].
  • The pharmacologic profile of the new class of phosphodiesterase (PDE) inhibitors-specifically PDE5 inhibitors-and their potential effects on hemodynamic variables have therefore become significant factors in therapeutic decision making [8].
  • Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association [9]?
  • As a consequence, the efficacy and safety of the PDE5 inhibitor sildenafil in the treatment of symptoms of female sexual dysfunction (FSD), including female sexual arousal disorders (FSAD), have been evaluated [10].

High impact information on PDE5A

  • Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions [11].
  • PKA and PKG, which mediate relaxation, act upstream to desensitize the receptors (VPAC(2) and NPR-C), inhibit adenylyl and guanylyl cyclase activities, and stimulate cAMP-specific PDE3 and PDE4 and cGMP-specific PDE5 activities [12].
  • Activated PDE5 showed higher sensitivity towards sildenafil than non-activated PDE5 [13].
  • Here, we identify cyclic GMP-dependent protein kinase I as the kinase responsible for the NO-induced PDE5 phosphorylation [14].
  • cGMP-specific, cGMP-binding phosphodiesterase (PDE5) regulates such physiological processes as smooth muscle relaxation and neuronal survival [13].

Chemical compound and disease context of PDE5A


Biological context of PDE5A

  • By sequence homology in the catalytic domain, PDE9A is almost equidistant from all eight known mammalian PDE families but is most similar to PDE8A (34% amino acid identity) and least like PDE5A (28% amino acid identity) [20].
  • PDE5A maps to chromosome 4q 25-27 [21].
  • CONCLUSIONS: Very high expression levels of PDE3A and PDE5A in human cavernous tissue underscore the physiological importance of these enzymes for the regulation of penile erection, emphasizing their therapeutical and pharmacological relevance [6].
  • Identification of three alternative first exons and an intronic promoter of human PDE5A gene [22].
  • We examined the tissue distribution of the two variants of human PDE5A in adult and fetal humans [23].

Anatomical context of PDE5A


Associations of PDE5A with chemical compounds


Regulatory relationships of PDE5A

  • For example, we have recently found that PDE5 is expressed in all Purkinje neurons while PDE1B is expressed in only a subset of these neurons [29].
  • In the presence of 1 mM EGTA, gustin activated cAMP PDE 5- to 6-fold, but the activating ability was completely lost after gustin was heated at 100 degrees C for 5 min [30].

Other interactions of PDE5A

  • PDE9A lacks a region homologous to the allosteric cGMP-binding regulatory regions found in the cGMP-binding PDEs: PDE2, PDE5, and PDE6 [20].
  • Therefore, the GAFa domain of PDE5A adopts a structure similar to the GAFb domain of PDE2A, and provides the sole site for cGMP binding in PDE5A [1].
  • The exon organization of the PDE11A catalytic domain was very similar to those of PDE5A and PDE6B [31].
  • PDE5A gene encodes type 5 phosphodiesterase (PDE5), the principal cGMP-catalyzing enzyme in the penis and the primary target of sildenafil (Viagra) [26].
  • The selectivity ratio vs PDE-5 is more than 10 000 for PDE-1 through PDE-4 and PDE-7 through PDE-10 and 780 for PDE-6 [32].

Analytical, diagnostic and therapeutic context of PDE5A


  1. Modeling and mutational analysis of the GAF domain of the cGMP-binding, cGMP-specific phosphodiesterase, PDE5. Sopory, S., Balaji, S., Srinivasan, N., Visweswariah, S.S. FEBS Lett. (2003) [Pubmed]
  2. Exisulind, a novel proapoptotic drug, inhibits rat urinary bladder tumorigenesis. Piazza, G.A., Thompson, W.J., Pamukcu, R., Alila, H.W., Whitehead, C.M., Liu, L., Fetter, J.R., Gresh, W.E., Klein-Szanto, A.J., Farnell, D.R., Eto, I., Grubbs, C.J. Cancer Res. (2001) [Pubmed]
  3. Life after PDE4: overcoming adverse events with dual-specificity phosphodiesterase inhibitors. Giembycz, M.A. Current opinion in pharmacology. (2005) [Pubmed]
  4. Tissue expression, distribution, and regulation of PDE5. Lin, C.S. Int. J. Impot. Res. (2004) [Pubmed]
  5. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Wharton, J., Strange, J.W., Møller, G.M., Growcott, E.J., Ren, X., Franklyn, A.P., Phillips, S.C., Wilkins, M.R. Am. J. Respir. Crit. Care Med. (2005) [Pubmed]
  6. Gene expression of the phosphodiesterases 3A and 5A in human corpus cavernosum penis. Küthe, A., Mägert, H., Uckert, S., Forssmann, W.G., Stief, C.G., Jonas, U. Eur. Urol. (2000) [Pubmed]
  7. Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. Patil, C.S., Singh, V.P., Kulkarni, S.K. Pharmacological reports : PR. (2006) [Pubmed]
  8. Sildenafil in patients with cardiovascular disease. Brindis, R.G., Kloner, R.A. Am. J. Cardiol. (2003) [Pubmed]
  9. Transient global amnesia after intake of tadalafil, a PDE-5 inhibitor: a possible association? Schiefer, J., Sparing, R. Int. J. Impot. Res. (2005) [Pubmed]
  10. Phosphodiesterase inhibitors in female sexual dysfunction. Mayer, M., Stief, C.G., Truss, M.C., Uckert, S. World journal of urology. (2005) [Pubmed]
  11. Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function. Serafini, P., Meckel, K., Kelso, M., Noonan, K., Califano, J., Koch, W., Dolcetti, L., Bronte, V., Borrello, I. J. Exp. Med. (2006) [Pubmed]
  12. Signaling for contraction and relaxation in smooth muscle of the gut. Murthy, K.S. Annu. Rev. Physiol. (2006) [Pubmed]
  13. PDE5 is converted to an activated state upon cGMP binding to the GAF A domain. Rybalkin, S.D., Rybalkina, I.G., Shimizu-Albergine, M., Tang, X.B., Beavo, J.A. EMBO J. (2003) [Pubmed]
  14. Direct activation of PDE5 by cGMP: long-term effects within NO/cGMP signaling. Mullershausen, F., Friebe, A., Feil, R., Thompson, W.J., Hofmann, F., Koesling, D. J. Cell Biol. (2003) [Pubmed]
  15. Phosphodiesterase isoenzymes as pharmacological targets in the treatment of male erectile dysfunction. Uckert, S., Küthe, A., Stief, C.G., Jonas, U. World journal of urology. (2001) [Pubmed]
  16. Cyclic-3',5'-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Dousa, T.P. Kidney Int. (1999) [Pubmed]
  17. Androgens regulate phosphodiesterase type 5 expression and functional activity in corpora cavernosa. Morelli, A., Filippi, S., Mancina, R., Luconi, M., Vignozzi, L., Marini, M., Orlando, C., Vannelli, G.B., Aversa, A., Natali, A., Forti, G., Giorgi, M., Jannini, E.A., Ledda, F., Maggi, M. Endocrinology (2004) [Pubmed]
  18. A cyclic nucleotide PDE5 inhibitor corrects defective mucin secretion in submandibular cells containing antibody directed against the cystic fibrosis transmembrane conductance regulator protein. McPherson, M.A., Pereira, M.M., Lloyd Mills, C., Murray, K.J., Dormer, R.L. FEBS Lett. (1999) [Pubmed]
  19. Expression and functional activity of phosphodiesterase type 5 in human and rabbit vas deferens. Mancina, R., Filippi, S., Marini, M., Morelli, A., Vignozzi, L., Salonia, A., Montorsi, F., Mondaini, N., Vannelli, G.B., Donati, S., Lotti, F., Forti, G., Maggi, M. Mol. Hum. Reprod. (2005) [Pubmed]
  20. Isolation and characterization of PDE9A, a novel human cGMP-specific phosphodiesterase. Fisher, D.A., Smith, J.F., Pillar, J.S., St Denis, S.H., Cheng, J.B. J. Biol. Chem. (1998) [Pubmed]
  21. Isolation and characterization of cDNAs encoding PDE5A, a human cGMP-binding, cGMP-specific 3',5'-cyclic nucleotide phosphodiesterase. Loughney, K., Hill, T.R., Florio, V.A., Uher, L., Rosman, G.J., Wolda, S.L., Jones, B.A., Howard, M.L., McAllister-Lucas, L.M., Sonnenburg, W.K., Francis, S.H., Corbin, J.D., Beavo, J.A., Ferguson, K. Gene (1998) [Pubmed]
  22. Identification of three alternative first exons and an intronic promoter of human PDE5A gene. Lin, C.S., Lau, A., Tu, R., Lue, T.F. Biochem. Biophys. Res. Commun. (2000) [Pubmed]
  23. Genomic origin and transcriptional regulation of two variants of cGMP-binding cGMP-specific phosphodiesterases. Kotera, J., Fujishige, K., Imai, Y., Kawai, E., Michibata, H., Akatsuka, H., Yanaka, N., Omori, K. Eur. J. Biochem. (1999) [Pubmed]
  24. 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]
  25. Expression, structure and chromosomal localization of the human cGMP-binding cGMP-specific phosphodiesterase PDE5A gene. Yanaka, N., Kotera, J., Ohtsuka, A., Akatsuka, H., Imai, Y., Michibata, H., Fujishige, K., Kawai, E., Takebayashi, S., Okumura, K., Omori, K. Eur. J. Biochem. (1998) [Pubmed]
  26. Identification and regulation of human PDE5A gene promoter. Lin, C.S., Chow, S., Lau, A., Tu, R., Lue, T.F. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  27. Crystal structure of phosphodiesterase 9 shows orientation variation of inhibitor 3-isobutyl-1-methylxanthine binding. Huai, Q., Wang, H., Zhang, W., Colman, R.W., Robinson, H., Ke, H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  28. Structural basis for the activity of drugs that inhibit phosphodiesterases. Card, G.L., England, B.P., Suzuki, Y., Fong, D., Powell, B., Lee, B., Luu, C., Tabrizizad, M., Gillette, S., Ibrahim, P.N., Artis, D.R., Bollag, G., Milburn, M.V., Kim, S.H., Schlessinger, J., Zhang, K.Y. Structure (Camb.) (2004) [Pubmed]
  29. Specific localized expression of cGMP PDEs in Purkinje neurons and macrophages. Bender, A.T., Beavo, J.A. Neurochem. Int. (2004) [Pubmed]
  30. Human salivary gustin is a potent activator of calmodulin-dependent brain phosphodiesterase. Law, J.S., Nelson, N., Watanabe, K., Henkin, R.I. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  31. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Yuasa, K., Kanoh, Y., Okumura, K., Omori, K. Eur. J. Biochem. (2001) [Pubmed]
  32. IC351 (tadalafil, Cialis): update on clinical experience. Porst, H. Int. J. Impot. Res. (2002) [Pubmed]
  33. Inhibitory effects of furoquinoline alkaloids from Melicope confusa and Dictamnus albus against human phosphodiesterase 5 (hPDE5A) in vitro. Nam, K.W., Je, K.H., Shin, Y.J., Kang, S.S., Mar, W. Arch. Pharm. Res. (2005) [Pubmed]
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