Key points are not available for this paper at this time.
The advent of the medication, sildenafil, 1Tradename VIAGRA™. 1Tradename VIAGRA™. for treatment of male impotence has attracted widespread attention. This agent potently inhibits a cGMP-binding cGMP-specific phosphodiesterase (PDE5). 2The abbreviations used are: PDE, 3′:5′-cyclic nucleotide phosphodiesterase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; IBMX, 3-isobutyl-1-methylxanthine 2The abbreviations used are: PDE, 3′:5′-cyclic nucleotide phosphodiesterase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; IBMX, 3-isobutyl-1-methylxanthine PDE5 is particularly abundant in smooth muscle, which is enriched in other components of the cGMP signaling cascade. The characteristics of PDE5, its relationship to other PDEs, its role in cGMP signaling, and its involvement in the efficacious action of sildenafil on corpus cavernosum and vascular smooth muscle resulting in penile erection are the subjects of this review. Cyclic GMP has emerged recently as a principal focus in signal transduction. Much of this attention has derived from the fact that most of the non-lytic physiological effects of nitric oxide (Fig.1) and all of the characterized effects of natriuretic peptides and guanylins are mediated by cGMP. In addition to the classical regulatory roles ascribed to cGMP such as stimulation of smooth muscle relaxation, neutrophil degranulation, inhibition of platelet aggregation, and initiation of visual signal transduction, numerous other physiological roles have recently been uncovered (1Schultz K.D. Schultz K. Schultz G. Nature. 1977; 265: 750-751Crossref PubMed Scopus (333) Google Scholar, 2Lincoln T.M. Cornwell T.L. FASEB J. 1993; 7: 328-338Crossref PubMed Scopus (539) Google Scholar, 3Francis S.H. Corbin J.D. Murad F. Cyclic GMP: Synthesis, Metabolism and Function. Academic Press, Orlando, FL1993: 115-170Google Scholar, 4Lohmann S.M. Vaandrager A.B. Smolenski A. Walter U. de Jonge H.R. 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Intracellular receptors for cGMP include cGMP-dependent protein kinases (PKG), cyclic nucleotide-gated channels, and cGMP-binding PDEs; cGMP may also cross-activate cAMP pathways by binding to cAMP-binding sites on cAMP receptors such as cAMP-dependent protein kinases (PKA) (11Jiang H. Colbran J.L. Francis S.H. Corbin J.D. J. Biol. Chem. 1992; 267: 1015-1019Abstract Full Text PDF PubMed Google Scholar). Tissue cGMP levels are determined by a balance between the activities of the guanylyl cyclases that catalyze formation of cGMP from GTP and the cyclic nucleotide PDEs that catalyze the breakdown of cGMP (Fig. 1). The combination of a stimulator of guanylyl cyclase and a cGMP PDE inhibitor such as sildenafil produces synergistic enhancement of tissue cGMP levels (12Jeremy J.Y. Ballard S.A. Naylor A.M. Miller M.A. Angelini G.D. Br. J. Urol. 1997; 79: 958-963Crossref PubMed Google Scholar). PDEs were first detected by Sutherland and co-workers (13Rall T.W. Sutherland E.W. J. Biol. 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Some PDEs are highly specific for hydrolysis of cAMP (PDE4, PDE7, PDE8), some are highly cGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1, PDE2, PDE3, PDE10). All of the characterized mammalian PDEs are dimeric, but the importance of the dimeric structure for function in each of the PDEs is unknown. Each PDE has a conserved catalytic domain of ∼270 amino acids with a high degree of conservation (25–30%) of amino acid sequence among PDE families, which is located carboxyl-terminal to its regulatory domain. Activators of certain PDEs appear to relieve the influence of autoinhibitory domains located within the enzyme structures (27Sonnenburg W.K. Seger D. Kwak K.S. Huang J. Charbonneau H. Beavo J.A. J. Biol. Chem. 1995; 270: 30989-31000Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 28Jin S.-L.C. Swinnen J.V. Conti M. J. Biol. Chem. 1992; 267: 18929-18939Abstract Full Text PDF PubMed Google Scholar). PDEs cleave the cyclic nucleotide phosphodiester bond between the phosphorus and oxygen atoms at the 3′-position with inversion of configuration at the phosphorus atom (29Goldberg N.D. Walseth T.F. Stephenson J.H. Krick T.P. Graff G. J. Biol. Chem. 1980; 255: 10344-10347Abstract Full Text PDF PubMed Google Scholar, 30Burgers P.M. Eckstein F. Hunneman D.H. Baraniak J. Kinas R.W. Lesiak K. Stec W.J. J. Biol. Chem. 1979; 254: 9959-9961Abstract Full Text PDF PubMed Google Scholar). This apparently results from an in-line nucleophilic attack by the OH− of ionized H2O. It has been proposed that metals bound in the conserved metal binding motifs within PDEs facilitate the production of the attacking OH− (31Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). The kinetic properties of catalysis are consistent with a random order mechanism with respect to cyclic nucleotide and the divalent cation(s) that are required for catalysis (32Srivastava D. Fox D.A. Hurwitz R.L. Biochem. J. 1995; 308: 653-658Crossref PubMed Scopus (23) Google Scholar). The catalytic domains of all known mammalian PDEs contain two sequences (HX 3HX n(E/D)) arranged in tandem, each of which resembles the single Zn2+-binding site of metalloendoproteases such as thermolysin (31Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar). PDE5 specifically binds Zn2+, and the catalytic activities of PDE4, PDE5, and PDE6 are supported by submicromolar concentrations of Zn2+ (31Francis S.H. Colbran J.L. McAllister-Lucas L.M. Corbin J.D. J. Biol. Chem. 1994; 269: 22477-22480Abstract Full Text PDF PubMed Google Scholar, 33Percival M.D. Yeh B. Falgueyret J.P. Biochem. Biophys. Res. Commun. 1997; 241: 175-180Crossref PubMed Scopus (56) Google Scholar). 4S. Francis, unpublished results. 4S. Francis, unpublished results.Whether each of the Zn2+ binding motifs binds Zn2+ independently or whether the two motifs interact to form a novel Zn2+-binding site is not known. The catalytic mechanism for cleaving phosphodiester bonds of cyclic nucleotides by PDEs may be similar to that of certain proteases for cleaving the amide ester of peptides, but the presence of two Zn2+ motifs arranged in tandem in PDEs is unprecedented. The group of Sutherland and Rall (34Berthet J. Sutherland E.W. Rall T.W. J. Biol. Chem. 1957; 229: 351-361Abstract Full Text PDF PubMed Google Scholar), in the late 1950s, was the first to realize that at least part of the mechanism(s) whereby caffeine enhanced the effect of glucagon, a stimulator of adenylyl cyclase, on cAMP accumulation and glycogenolysis in liver involved inhibition of cAMP PDE activity. Since that time chemists have synthesized thousands of PDE inhibitors, including the widely used 3-isobutyl-1-methylxanthine (IBMX). Many of these compounds, as well as caffeine, are non-selective and inhibit many of the PDE families. One important advance in PDE research has been the discovery/design of family-specific inhibitors such as the PDE4 inhibitor rolipram and the PDE5 inhibitor sildenafil. Precise modulation of PDE function in cells is critical for maintaining cyclic nucleotide levels within a narrow rate-limiting range of concentrations. Increases in cGMP of 2–4-fold above the basal level will usually produce a maximum physiological response. There are three general schemes by which PDEs are regulated: (a) regulation by substrate availability, such as by stimulation of PDE activity by mass action after elevation of cyclic nucleotide levels or by alteration in the rate of hydrolysis of one cyclic nucleotide of by which with of the specificity PDEs PDE2, regulation by that signaling for in stimulation of activity by E. Belfrage P. Manganiello V.C. J. Biol. Chem. 1997; 272: 6823-6826Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar), stimulation of PDE6 activity by the A. I. M.W. P. J. Biol. Chem. 1980; 255: Full Text PDF PubMed Google Scholar), which PDE6 with this or stimulation of activity by with such as by of PDE3, or PDE4 by after cAMP elevation M. Nemoz G. Sette C. Vicini E. Endocr. Rev. 1995; 16: 370-389Crossref PubMed Scopus (316) Google Scholar, 18Degerman E. Belfrage P. Manganiello V.C. J. Biol. Chem. 1997; 272: 6823-6826Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, T.W. 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It is that and specific PDE5 inhibitors or of the other components of the cGMP will be in the to as well as other that smooth muscle Ballard and for are to and for into the of cyclic caffeine, and also and for
Corbin et al. (Sat,) studied this question.