Molecular Properties of Cyclic Nucleotide Phosphodiesterase Isozymes

  • Samuel J. Strada
  • Philip A. Kithas
  • Michael E. Whalin
  • W. Joseph Thompson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 255)


Mammalian cells contain multiple molecular forms of cyclic nucleotide phosphodiesterase that differ in substrate specificity and kinetic and regulatory properties. Calcium/calmodulin and cyclic GMP are important regulators of the hydrolysis of cyclic AMP by either stimulating or inhibiting the activity of distinct forms of phosphodiesterase. Several isozymes of cyclic nucleotide phosphodiesterase have been purified to apparent homogeneity. Although some sequence homology is observed the isozymes appear genetically distinct by immunological criteria. Cyclic AMP- and calmodulin-dependent protein kinases can phosphorylate these enzymes and alter their kinetic and regulatory properties. Both tissue specificity and pharmacological selectivity of isozymes have been demonstrated for several drugs. In certain cases, e.g. cardiac muscle, the selective inhibition of a high affinity cAMP phosphodiesterase activity in a specific subcellular fraction correlates with pharmacologic responses. The results from molecular and pharmacologic studies of cyclic nucleotide phosphodiesterases have indeed expanded the role this system of isoenzymes exerts in the regulation of cellular function.


Cyclic Nucleotide Phosphodiesterase Activity Cyclic Nucleotide Phosphodiesterase Multiple Molecular Form cAMP Hydrolysis 
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  1. 1.
    Strada, S. J. and Thompson, W. J., “Advances cyclic Nucleotide Phosphorylation Research 16, Nomenclature Recommendation,” p. vi (1984).Google Scholar
  2. 2.
    Appleman, M. M., Allan, E. H., Ariano, M.A., Ong, K. K., Tusang, C. A., Weber, H. W., and Whitson, R. H., Insulin Control of Cyclic AMP Phosphodiesterase, Adv. Cyc. Nuc. Prot. Phos. Res., 16:149–158 (1984).Google Scholar
  3. 3.
    Weber, H. W. and Appleman, M. M., Insulin-Dependent and Insulin-Independent Low Km Cyclic AMP Phosphodiesterase from Rat Adipose Tissue, J. Biol. Chem., 257:5339–5341 (1982).PubMedGoogle Scholar
  4. 4.
    Wang, J. H. and Waisman, D. M., Calmodulin and Its Role in the Second Messenger System, Curr. Topics in Cell Res., 15:47–107 (1979).Google Scholar
  5. 5.
    Hurley, J. B. and Stryer, L., Purification and Characterization of the Gamma Regulatory Subunit of the Cyclic GMP Phosphodiesterase from Retinal Rod Outer Segments, J. Biol. Chem., 257:11094–11099 (1982).PubMedGoogle Scholar
  6. 6.
    Alvarez, R., Banerjee, G. L., Bruno, J. J., Jones, G. L., Liittschwager, K., Strosberg, A. M., and Venuti, M. C., A Potent and Selective Inhibitor of Cyclic AMP Phosphodiesterase with Potential Cardiotonic and Antithrombic Properties, Molec. Pharm., 29:554–560 (1986).PubMedGoogle Scholar
  7. 7.
    Weishaar, R. E., Cain, M. H., and Bristol, J.A., A new Generation of Phosphodiesterase Inhibitors: Multiple Molecular Forms of Phosphodiesterase and the Potential for Drug Selectivity, J. Med. Chem., 28:537–545 (1985).PubMedCrossRefGoogle Scholar
  8. 8.
    Pang, D. C., Cyclic AMP and Cyclic GMP Phosphodiesterases: Target for Drug Development, Drug Devel. Res., 12:85–92 (1988).CrossRefGoogle Scholar
  9. 9.
    Sharma, R. K., Wang, T. H., Wirch, E., and Wang, J. H., Purification and Properties of Bovein Brain Calmodulin-Dependent Cyclic Nucleotide Phosphodiesterase, J. Biol. Chem., 255:5916–5923 (1980).PubMedGoogle Scholar
  10. 10.
    Shenolikar, S., Thompson, W. J., and Strada, S. J., Characterization of a Novel Form of Ca2+-Calmodulin Stimulated Cyclic GMP Phosphodiesterase from Bovine Brain, Biochemistry, 24:672–678 (1985).PubMedCrossRefGoogle Scholar
  11. 11.
    Ho, H. C, Wirch, E., Stevens, F. C, and Wang, J. H., Purification of a Ca++-Activatable Cyclic Nucleotide Phosphodiesterase from Bovine Heart by Specific Interaction with its Calcium Dependent Modulator Protein, J. Biol. Chem., 252:43–50 (1977).PubMedGoogle Scholar
  12. 12.
    Hanson, R.S., Charbonneau, H., and Beavo, J.A., Purification of Calmodulin-Stimulated Cyclic Nucleotide Phosphodiesterase by Monoclonal Antibody Affinity Chromatography, Meth. Enzymol., 159:543–557 (1988).CrossRefGoogle Scholar
  13. 13.
    Sharma, R. K. and Wang, J. H., Purification and Characterization of Bovine Lung Calmodulin-Dependent cyclic Nucleotide Phosphodiesterase, J. Biol. Chem., 261: 14160–14166 (1986).PubMedGoogle Scholar
  14. 14.
    Sharma, R. K. and Wang, J. H., Calmodulin and Ca++-Dependent Phosphorylation and Dephosphorylation of 63-kDa Subunit-Containing Bovine Brain Calmodulin-Stimulated cyclic Nucleotide Phosphodiesterase Isozyme, J. Biol. Chem., 261:1322–1328 (1986).PubMedGoogle Scholar
  15. 15.
    Saitoh, Y., Hardman, J. G., and Wells, J. N., Differences in the Association of Calmodulin with Cyclic Nucleotide Phosphodiesterase in Relaxed and Contracted Arterial Strips, Biochemistry, 24:1613–1618 (1985).PubMedCrossRefGoogle Scholar
  16. 16.
    Hidaka, H., Inagaki, M., Nishikawa, M. and Tanaka, T., Selective Inhibitors of Calmodulin-Dependent Phosphodiesterase and Other Enzymes, Meth. Enzymol., 159:652–660 (1988).PubMedCrossRefGoogle Scholar
  17. 17.
    Norman, J. A., Ansell, J., Stone, G. A., Wennogle, L. P., and Wasley, J. W. F., CGS 9343B, a Novel, Potent, and Selective Inhibitor of Calmodulin Activity, Mol. Pharmacol., 31:535–540 (1987).PubMedGoogle Scholar
  18. 18.
    Martins, T. J., Mumby, M. D., and Beavo, J. A., Purification and Characterization of a Cyclic GMP-Stimulated Cyclic Nucleotide Phosphodiesterase from Bovine Tissues, J. Biol. Chem., 257:1973–1979 (1982).PubMedGoogle Scholar
  19. 19.
    Miot, F., Van Haastert, J. M., and Erneaux, C., Specificity of cGMP Binding to a Purified cGMP-Stimulated Phosphodiesterase from Bovine Adrenal Tissue, Eur. J. Biochem., 149:59–65 (1985).PubMedCrossRefGoogle Scholar
  20. 20.
    Harrison, S. A., Beier, N., Martins, T. J., and Beavo, J. A., Isolation and Comparison of Bovine Heart cGMP-Inhibited and cGMP-Stimulated Phosphodiesterases, Meth. Enzymol., 159:685–702 (1988).PubMedCrossRefGoogle Scholar
  21. 21.
    Yamamoto, T., Manganiello, V. C., and Vaughan, M., Purification and Characterization of Cyclic GMP-Stimulated Cyclic Nucleotide Phosphodieterase From Cat Liver, J. Biol. Chem., 258:12526–12533 (1983).PubMedGoogle Scholar
  22. 22.
    Mumby, M. C., Martins, T. J., Chang, M. L., and Beavo, J. A., Identification of cGMP-Stimulated Cyclic Nucleotide Phosphodiesterase in Lung Tissue with Monoclonal Antibodies, J. Biol. Chem., 257:13283–13290 (1982).PubMedGoogle Scholar
  23. 23.
    Pyne, N. J., Cooper, M. E., and Houslay, M. D., Identification and Characterization, of Both the Cytosolic and Particulate Forms of Cyclic GMP-Stimulated Cyclic AMP Phosphodiesterase from Rat Liver, Biochem. J., 234:325–334 (1986).PubMedGoogle Scholar
  24. 24.
    Whalin, M. E., Strada, S. J., and Thompson, W. J., Purification and Characterization of Membrane Bound, Rabbit Brain cGMP Activatable (Type II) Cyclic Nucleotide Phosphodiesterase, Biochim. Biophys. Acta, In Press (1988).Google Scholar
  25. 25.
    Wada, H., Osborne, J. C., Jr., and Manganiello, V. C., Effects of Temperature on Allosteric and Catalytic Properties of the cGMP-Stimulated Cyclic Nucleotide Phosphodiesterase From Calf Liver, J. Biol. Chem., 262:5139–5144 (1987).PubMedGoogle Scholar
  26. 26.
    Erneaux, C., Miot, F., Van Haastert, P. J. M., and Jastoff, B., The Binding of Cyclic Nucleotide Analgos to a Purified Cyclic GMP-Stimulated Phosphodiesterase from Bovine Adrenal Tissue, J. Cyclic Nuc. Res., 10:463–472 (1985).Google Scholar
  27. 27.
    Hartzeil, H. C. and Fischmeister, R., 1986, Opposite Effects of Cyclic GMP and Cyclic AMP on Ca2+ Current in Single Heart Cells, Nature, 323:273–275 (1986).CrossRefGoogle Scholar
  28. 28.
    Levitan, I. B., Modulation of Ion Channels in Neurons and Other Cells, Ann. Rev. Neurosci., 11:119–136 (1988).PubMedCrossRefGoogle Scholar
  29. 29.
    Yamamoto, T., Yamamoto, S., Osborne, J. C., and Manganiello, V. C., Complex Effects of Inhibitors on Cyclic GMP-Stimulated Cyclic Nucleotide Phosphodiesterase, J. Biol. Chern., 258: 14173–14177 (1983).Google Scholar
  30. 30.
    Erneaux, C, Couchie, D., Dumont, J. E., Baraniak, J., Stec, W.J., Abbad, E. G., Petridis, G., and Jastorff, B., Specificity of Cyclic GMP Activation of a Multi-Substrate Cyclic Nucleotide Phosphodiesterase from Rat Liver, Eur. J. Biochem., 115:503–510 (1981).CrossRefGoogle Scholar
  31. 31.
    Yamamoto, T., Yamamoto, S., Manganiello, V. C., and Vaughan, M., Effects of Fatty Acids on Activity of cGMP-Stimulated Cyclic Nucleotide Phosphodiesterase From Calf Liver, Arch. Biochem. Biophys., 229:81–89 (1984).PubMedCrossRefGoogle Scholar
  32. 32.
    Stryer, L. The Cyclic GMP Cascade of Vision, Ann. Rev. Neurosci. 9:87–119 (1986).PubMedCrossRefGoogle Scholar
  33. 33.
    Baehr, W., Morita, E. A., Swanson, R. J., and Applebury, M. L., Characterization of Bovine Rod Outer Segment G-protein, J. Biol. Chem., 257:6452–6460 (1982).PubMedGoogle Scholar
  34. 34.
    Charbonneau, H., Beir, N., Walsh, K., and Beavo, J.A., Identification of a Conserved Domain Among Cyclic Nucleotide Phosphodiesterases from Diverse Species, Proc. Nat. Acad. Sci., 83:9308–9312 (1986).PubMedCrossRefGoogle Scholar
  35. 35.
    Ovchinnikov, Yu A., Gubanov, V. V., Khramtsou, N. V., Ischenko, K. A., Zagranichny, V. E., Muradov, K. G., Shuvaeva, T. M., Lipkin, V. M., Cyclic GMP Phosphodiesterase from Bovine Retina-Amino Acid Sequence of the α-Subunit and Nucleotide Sequence of the Corresponding cDNA, FEB’S Lett., 223:169–173 (1987).CrossRefGoogle Scholar
  36. 36.
    Ovchinnikov, Yu A., Lipkin, V. M., Kumarev, V. P., Gubanov, V. V., Khramtsov, N. V., Akhmedov, N. B., Zagranichny, V. E. and Muradov, K. G., Cyclic GMP Phosphodiesterase from Cattle Retina-Amino Acid Sequence of the Y-Subunit and Nucleotide Sequence of the Corresponding cDNA, FEBS Lett., 204:288–292 (1986).PubMedCrossRefGoogle Scholar
  37. 38.
    Tyminski, P. N., Latimer, L. H., and O’Brien, D. F., Reconstitution of Rhodopsin and the cGMP Cascade in Polymerized Bilayer Membranes, Biochem., 27:2696–2705 (1988).CrossRefGoogle Scholar
  38. 39.
    Francis, S. H., Effectors of Rat Lung cGMP Binding Protein-Phosphodiesterase, Curr. Top. Cell. Reg., 26:247–262 (1985).Google Scholar
  39. 40.
    Francis, S. H. and Corbin, J., 1988, purification of cGMP-Binding Protein Phosphodiesterase From Rat Lung, Meth. Enzymol., 159:722–729 (1988).PubMedCrossRefGoogle Scholar
  40. 41.
    Epstein, P. M., Strada, S. J., Sarada, K., and Thompson, W. J., Catalytic and Kinetic Properties of Purified High-Affinity Cyclic AMP Phosphodiesterase from Dog Kidney, Arch. Bioc. Biops., 218:119–133 (1982).CrossRefGoogle Scholar
  41. 42.
    Thompson, W. J., Shen, C-C., and Strada, S. J., Preparation of Dog Kidney High-Affinity cAMP Phosphodiesterase, Meth. Enzymol., 159:760–766 (1988).PubMedCrossRefGoogle Scholar
  42. 43.
    Schultz, J. E. and Folkers, G., Unusual Stereospecificity of the Potential Antidepressant Rolipram on the cyclic AMP Generating System from Rat Brain Cortex, Pharmacopsychiat., 21:83–86 (1988).CrossRefGoogle Scholar
  43. 44.
    Kithas, P. A., Artman, M., Thompson, W. J., and Strada, S. J., Subcellular Distribution of High-Affinity Type IV Cyclic AMP Phosphodiesterase Activities in Rabbit Ventricular Myocardium: Relations to the Effects of Cardiotonic Drugs, Circ. Res., 62:782–789 (1988).PubMedGoogle Scholar
  44. 45.
    Robertson, D. W., Jones, N. D., Krushinski, J. H., Pollock, G. D., Swartzendruber, J. K., and Hayes, J. S., Molecular Structure of the Dihydropyridazinone Cardiotonic 1,3-Dihydro-3,3-Dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one, a Potent Inhibitor of Cyclic AMP Phosphodiesterase, J. Med. Chem., 30:623–627 (1987).PubMedCrossRefGoogle Scholar
  45. 46.
    Moos, W. H., Humblet, C. C, Sircar, I., Rithner, C, Weishaar, R. E., Bristol, J. A., and McPhail, A. T., Cardiotonic Agents 8. Sélective Inhibitors of Adenosine 3′,5′-Cyclic Phosphate Phosphodiesterase III. Elaboration of a Five-Point Model for Positive Inotropic Activity, J. Med. Chem., 30:1963–1972 (1987).PubMedCrossRefGoogle Scholar
  46. 47.
    Earhart, P. W., Hagedorn, III, A. A., and Sabio, M., Cardiotonic Agents 3. A Topographical Model of the Cardiac cAMP Phosphodiesterase Receptor, Mol. Pharmacol., 33:1–13 (1988).Google Scholar
  47. 48.
    Kauffman, R. F., Crowe, G. V., Utterback, B. G., and Robertson, D. W., LY195115: A Potent, Selective Inhibitor of Cyclic Nucleotide Phosphodiesterase Located in the Sarcoplasmic Reticulum, Mol. Pharmacol., 30:609–616 (1987).Google Scholar
  48. 49.
    Kithas, P. A., Artman, M., Thompson, W. J., and Strada, S. J., Subcellular Distribution of High-Affinity Type IV Cyclic AMP Phosphodiesterase Activities in Rabbit Ventricular Myocardium: Relations to Postnatal Maturation, J. Molec. Cell. Cardiol., In Press (1988).Google Scholar
  49. 50.
    Elks, M. L., Manganiello, V. C., and Vaughan, M., Effect of Dexamethasone on Adenosine 3′,5′-Monophosphate Content Phosphodiesterase Activities in 3T3-L1 Adipocytes, Endocrinol., 115:1350–1356 (1984).CrossRefGoogle Scholar
  50. 51.
    Gabbay, R. A. and Lardy, H. A., Site of Insulin Inhibition of cAMP-Stimulated Glycogenolysis, J. Biol. Chem., 259:6052–6055 (1984).PubMedGoogle Scholar
  51. 52.
    Lamer, J., Insulin Mediator-Fact or Fancy?, J. Cyclic Nucleo., 8:289–296 (1982).Google Scholar
  52. 53.
    Gettys, T. W., Blackmore, P. F., and Corbin, J. D., An Assessment of Phosphodiesterase Activity in situ After Treatment of Hepatocyte with Hormones, Am. J. Physiol., 254: (Endocrinol. Metab. 17):E449–E453 (1988).PubMedGoogle Scholar
  53. 54.
    Gettys, T. W., Blackmore, P. F., Redmon, J. B., Beebe, S. J. and Corbin, J. D., Short-Term Regulation of cAMP by Accelerated Degradation in Rat Tissues, J. Biol. Chem., 262:333–339 (1987).PubMedGoogle Scholar
  54. 55.
    Weber, H. W., Chung, F-Z, Day, K., and Appleman, M. M., Insulin Stimulation of Cyclic AMP Phosphodiesterase is Independent from the G-Protein Pathways Involved in Adenylate Cyclase Regulation, J. Cyc. Nuc. Prot. Phos. Res., 11:345–354 (1987).Google Scholar
  55. 56.
    Macphee, C. H., Reifsnyder, D. H., Moore, T. A., and Beavo, J. M., Intact Cell and Cell-Free Phosphorylation and Concomitant Activation of a Low Km, cAMP Phosphodiesterase Found in Human Platelets, J. Cyclic Nucleo. Prot. Phos. Res., 11:487–496 (1987).Google Scholar
  56. 57.
    Houslay, M. D., Wallace, A. V., Marchmont, R. J., Martin, B. R., and Heyworth, C M., Insulin Controls Intracellular Cyclic AMP Concentrations in Hepatocytes by Activating Specific Cyclic AMP Phosphodiesterases: Phosphorylation of the Peripheral Plasma Membrane Enzyme, Adv. Cyclic Nucleo., 16:159–176 (1984).Google Scholar
  57. 58.
    Cordle, S.R. and Corbin, J.D., Activation of cGMP-Insensitive Low Km Phosphodiesterase by cAMP-Dependent Protein Kinase, FASEB J., 2:1739 (1988).Google Scholar
  58. 59.
    Souness, J. E., Thompson, W. J., and Strada, S.J., Adipocyte Cyclic Nucleotide Phosphodiesterase Activation by Vanadate, J. Cyclic Nuc. Prot. Phos. Res., 10:383–396 (1985).Google Scholar
  59. 60.
    Harrison, S. A., Reifsnyder, D. H., Gallis, B., Cadd, G. G., and Beavo, J. A., Isolation and Characterization of Bovine Cardiac Muscle cGMP-Inhibited Phosphodiesterase: A Receptor for New Cardiotonic Drugs, Mol. Pharm., 29:506–514 (1986).Google Scholar
  60. 61.
    Degerman, E., Beifrage, P., Newman, A. H., Rice, K. C., and Manganiello, V. C., Purification of the Putative Hormone-Sensitive Cyclic AMP Phosphodiesterase from Rat Adipose Tissue Using a Derivative of Cilostamide as a Novel Affinity Ligand, J. Biol. Chem., 262:5797–5807 (1987).PubMedGoogle Scholar
  61. 62.
    Grant, P. G. and Coleman, R. W., Purification and Characterization of Human Platelet Cyclic Nucleotide Phosphodiesterase, Biochem., 23:1801–1807 (1984).CrossRefGoogle Scholar
  62. 63.
    Benelli, C, Lopez, S., Desbuquois, B., and Achagiotis, C., Changes in Low-Km CAMP Phosphodiesterase Activity in Liver Golgi ractions from Hyper-and Hypoinsulinemic Rats, Diabetes, 37:171–722 (1988).CrossRefGoogle Scholar
  63. 64.
    Fatemi, S. H., Insulin-Dependent Cyclic AMP Turnover in Isolated Rat Adipocytes, Cell. Mol. Biol., 31:153–161 (1985).PubMedGoogle Scholar
  64. 65.
    Hanifin, J. M., Atopic Dermatitis, J. All. Clin. Immun., 73:211–222 (1984).CrossRefGoogle Scholar
  65. 66.
    Holden, C. A., Chan, S. C, Norris, S., and Hanifin, J. M., Histamine Induced Elevation of Cyclic AMP Phosphodiesterase Activity in Human Monocytes, Agents and Action, 22:36–42 (1987).CrossRefGoogle Scholar
  66. 67.
    Chan, S. C, Hanifin, J. M., Holden, C., Peters, J. E., Thompson, W. J., and Hirshman, C. A., Elevated Leukocyte Phosphodiesterase as a Basis for Depressed Cyclic AMP Responses in the Basenjigreyhound Dog Model of Asthma, J. Allergy and Clin. Immunol., 76:148–158 (1985).CrossRefGoogle Scholar
  67. 68.
    Onali, P., Strada, S. J., Epstein, P. M., and Thompson, Purification and Characterization of High affinity Cyclic Nucleotide Phosphodiesterase from Human Myelogenous Leukemic Cells, Cancer Res., 45:1384–1391 (1985).PubMedGoogle Scholar
  68. 69.
    Epstein, P. M. and Hachisu, R., Cyclic Nucleotide Phosphodiesterase in Normal and Leukemic Human Lymphocytes and Lymphoblasts, Adv. Cyc. Nuc. Prot. Phos. Res., 16:303–324 (1984).Google Scholar

Copyright information

© Plenum Press, New York 1989

Authors and Affiliations

  • Samuel J. Strada
    • 1
  • Philip A. Kithas
    • 1
  • Michael E. Whalin
    • 1
  • W. Joseph Thompson
    • 1
  1. 1.Department of PharmacologyUniversity of South Alabama College of MedicineMobileUSA

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