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Physiol. Rev. 75: 725-748, 1995;
0031-9333/95 $15.00
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Physiological Reviews, Vol 75, 725-748, Copyright © 1995 by American Physiological Society

JOURNAL ARTICLE

Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms

J. A. Beavo
Department of Pharmacology, University of Washington, Seattle, USA.

In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide phosphodiesterases. In particular, the accumulating data showing that there are a large number of different phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.


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M. T. Lin, L. D. Longo, W. J. Pearce, and D. A. Hessinger
Ca2+-activated K+ channel-associated phosphatase and kinase activities during development
Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H414 - H425.
[Abstract] [Full Text] [PDF]

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 JGPHome page
D. Holcman and J. I. Korenbrot
The Limit of Photoreceptor Sensitivity: Molecular Mechanisms of Dark Noise in Retinal Cones
J. Gen. Physiol., May 31, 2005; 125(6): 641 - 660.
[Abstract] [Full Text] [PDF]

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 J. Exp. Biol.Home page
M. Anctil, I. Poulain, and C. Pelletier
Nitric oxide modulates peristaltic muscle activity associated with fluid circulation in the sea pansy Renilla koellikeri
J. Exp. Biol., May 15, 2005; 208(10): 2005 - 2017.
[Abstract] [Full Text] [PDF]

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 BloodHome page
J. Seybold, D. Thomas, M. Witzenrath, S. Boral, A. C. Hocke, A. Burger, A. Hatzelmann, H. Tenor, C. Schudt, M. Krull, et al.
Tumor necrosis factor-{alpha}-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability
Blood, May 1, 2005; 105(9): 3569 - 3576.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
H.-F. Tang, Y.-H. Song, J.-C. Chen, J.-Q. Chen, and P. Wang
Upregulation of Phosphodiesterase-4 in the Lung of Allergic Rats
Am. J. Respir. Crit. Care Med., April 15, 2005; 171(8): 823 - 828.
[Abstract] [Full Text] [PDF]

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 J. Neurosci.Home page
N. Zhang, A. Beuve, and E. Townes-Anderson
The Nitric Oxide-cGMP Signaling Pathway Differentially Regulates Presynaptic Structural Plasticity in Cone and Rod Cells
J. Neurosci., March 9, 2005; 25(10): 2761 - 2770.
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 J. Neurosci.Home page
M. del Pilar Gomez and E. Nasi
Calcium-Independent, cGMP-Mediated Light Adaptation in Invertebrate Ciliary Photoreceptors
J. Neurosci., February 23, 2005; 25(8): 2042 - 2049.
[Abstract] [Full Text] [PDF]

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 Am J Health Syst PharmHome page
D. L. Smull and U. P. Jorde
Concomitant use of nesiritide and milrinone in decompensated congestive heart failure
Am. J. Health Syst. Pharm., February 1, 2005; 62(3): 291 - 295.
[Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
G. A. Ross, P. Oishi, A. Azakie, S. Fratz, R. K. Fitzgerald, M. J. Johengen, C. Harmon, K. Hendricks-Munoz, J. Xu, S. M. Black, et al.
Endothelial alterations during inhaled NO in lambs with pulmonary hypertension: implications for rebound hypertension
Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L27 - L35.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Lung Cell. Mol. Physiol.Home page
P. G. Phillips, L. Long, M. R. Wilkins, and N. W. Morrell
cAMP phosphodiesterase inhibitors potentiate effects of prostacyclin analogs in hypoxic pulmonary vascular remodeling
Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L103 - L115.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
P. Wu and P. Wang
Per-Arnt-Sim domain-dependent association of cAMP-phosphodiesterase 8A1 with I{kappa}B proteins
PNAS, December 21, 2004; 101(51): 17634 - 17639.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
D. Huang, T. R. Hinds, S. E. Martinez, C. Doneanu, and J. A. Beavo
Molecular Determinants of cGMP Binding to Chicken Cone Photoreceptor Phosphodiesterase
J. Biol. Chem., November 12, 2004; 279(46): 48143 - 48151.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
J. Cheng, M. A. Thompson, H. J. Walker, C. E. Gray, M. M. Diaz Encarnacion, G. M. Warner, and J. P. Grande
Differential regulation of mesangial cell mitogenesis by cAMP phosphodiesterase isozymes 3 and 4
Am J Physiol Renal Physiol, November 1, 2004; 287(5): F940 - F953.
[Abstract] [Full Text] [PDF]

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 BloodHome page
B. O. Jensen, F. Selheim, S. O. Doskeland, A. R. L. Gear, and H. Holmsen
Protein kinase A mediates inhibition of the thrombin-induced platelet shape change by nitric oxide
Blood, November 1, 2004; 104(9): 2775 - 2782.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
H. A. Ghofrani, R. Voswinckel, F. Reichenberger, H. Olschewski, P. Haredza, B. Karadas, R. T. Schermuly, N. Weissmann, W. Seeger, and F. Grimminger
Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: A randomized prospective study
J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1488 - 1496.
[Abstract] [Full Text] [PDF]

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 Ann. Thorac. Surg.Home page
S. G. Raja and S. H. Nayak
Sildenafil: Emerging Cardiovascular Indications
Ann. Thorac. Surg., October 1, 2004; 78(4): 1496 - 1506.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
T. Matsumoto, K. Wakabayashi, T. Kobayashi, and K. Kamata
Diabetes-related changes in cAMP-dependent protein kinase activity and decrease in relaxation response in rat mesenteric artery
Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1064 - H1071.
[Abstract] [Full Text] [PDF]

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 ANN INTERN MEDHome page
H. A. Ghofrani, F. Reichenberger, M. G. Kohstall, E. H. Mrosek, T. Seeger, H. Olschewski, W. Seeger, and F. Grimminger
Sildenafil Increased Exercise Capacity during Hypoxia at Low Altitudes and at Mount Everest Base Camp: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial
Ann Intern Med, August 3, 2004; 141(3): 169 - 177.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
M. Mongillo, T. McSorley, S. Evellin, A. Sood, V. Lissandron, A. Terrin, E. Huston, A. Hannawacker, M. J. Lohse, T. Pozzan, et al.
Fluorescence Resonance Energy Transfer-Based Analysis of cAMP Dynamics in Live Neonatal Rat Cardiac Myocytes Reveals Distinct Functions of Compartmentalized Phosphodiesterases
Circ. Res., July 9, 2004; 95(1): 67 - 75.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
H. A. Ghofrani, J. Pepke-Zaba, J. A. Barbera, R. Channick, A. M. Keogh, M. A. Gomez-Sanchez, M. Kneussl, and F. Grimminger
Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension
J. Am. Coll. Cardiol., June 16, 2004; 43(12_Suppl_S): 68S - 72S.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Sahu
Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin
Endocrinology, June 1, 2004; 145(6): 2613 - 2620.
[Abstract] [Full Text] [PDF]

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 J. Thorac. Cardiovasc. Surg.Home page
S. Thelitz, J. M. Bekker, B. Ovadia, R. B. Stuart, M. J. Johengen, S. M. Black, and J. R. Fineman
Inhaled nitric oxide decreases pulmonary soluble guanylate cyclase protein levels in 1-month-old lambs
J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1285 - 1292.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
K. K. Meja, M. C. Catley, L. M. Cambridge, P. J. Barnes, H. Lum, R. Newton, and M. A. Giembycz
Adenovirus-Mediated Delivery and Expression of a cAMP-Dependent Protein Kinase Inhibitor Gene to BEAS-2B Epithelial Cells Abolishes the Anti-Inflammatory Effects of Rolipram, Salbutamol, and Prostaglandin E2: A Comparison with H-89
J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 833 - 844.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
C. E. Teixeira, J. S. Baracat, A. Zanesco, E. Antunes, and G. De Nucci
Atypical {beta}-Adrenoceptor Subtypes Mediate Relaxations of Rabbit Corpus Cavernosum
J. Pharmacol. Exp. Ther., May 1, 2004; 309(2): 587 - 593.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
X.-P. Ni, M. Safai, R. Rishi, C. Baylis, and M. H. Humphreys
Increased Activity of cGMP-Specific Phosphodiesterase (PDE5) Contributes to Resistance to Atrial Natriuretic Peptide Natriuresis in the Pregnant Rat
J. Am. Soc. Nephrol., May 1, 2004; 15(5): 1254 - 1260.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Heart Circ. Physiol.Home page
H.-L. Xu, V. Gavrilyuk, H. M. Wolde, V. L. Baughman, and D. A. Pelligrino
Regulation of rat pial arteriolar smooth muscle relaxation in vivo through multidrug resistance protein 5-mediated cGMP efflux
Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H2020 - H2027.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
R. T. Schermuly, K. P. Kreisselmeier, H. A. Ghofrani, A. Samidurai, S. Pullamsetti, N. Weissmann, C. Schudt, L. Ermert, W. Seeger, and F. Grimminger
Antiremodeling Effects of Iloprost and the Dual-Selective Phosphodiesterase 3/4 Inhibitor Tolafentrine in Chronic Experimental Pulmonary Hypertension
Circ. Res., April 30, 2004; 94(8): 1101 - 1108.
[Abstract] [Full Text] [PDF]

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 CMAJHome page
L. Fazio and G. Brock
Erectile dysfunction: management update
Can. Med. Assoc. J., April 27, 2004; 170(9): 1429 - 1437.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
M. Zaccolo
Use of Chimeric Fluorescent Proteins and Fluorescence Resonance Energy Transfer to Monitor Cellular Responses
Circ. Res., April 16, 2004; 94(7): 866 - 873.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
B. K. S. Sastry, C. Narasimhan, N. K. Reddy, and B. S. Raju
Clinical efficacy of sildenafil in primary pulmonary hypertension: A randomized, placebo-controlled, double-blind, crossover study
J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1149 - 1153.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
J. J. F. P. Luiken, S. L. M. Coort, J. Willems, W. A. Coumans, A. Bonen, and J. F. C. Glatz
Dipyridamole Alters Cardiac Substrate Preference by Inducing Translocation of FAT/CD36, but Not That of GLUT4
Mol. Pharmacol., March 1, 2004; 65(3): 639 - 645.
[Abstract] [Full Text] [PDF]

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 GeneticsHome page
A. M. Kays and K. A. Borkovich
Severe Impairment of Growth and Differentiation in a Neurospora crassa Mutant Lacking All Heterotrimeric G{alpha} Proteins
Genetics, March 1, 2004; 166(3): 1229 - 1240.
[Abstract] [Full Text] [PDF]

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 ChestHome page
H. H. Leuchte, M. Schwaiblmair, R. A. Baumgartner, C. F. Neurohr, T. Kolbe, and J. Behr
Hemodynamic Response to Sildenafil, Nitric Oxide, and Iloprost in Primary Pulmonary Hypertension
Chest, February 1, 2004; 125(2): 580 - 586.
[Abstract] [Full Text] [PDF]


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