Mechanisms of Pharmacologically Altering Calmodulin Activity

  • Walter C. Prozialeck
  • Benjamin Weiss


Considerable evidence has now accumulated indicating that calmodulin is the principal mediator of the effects of Ca2+ in most eukaryotic cells [for reviews see 3,8,24,25]. Since calmodulin plays such a fundamental role in cell biology, agents that inhibit its activity should produce important pharmacological effects. An understanding of the mechanisms by which drugs alter calmodulin activity may suggest new approaches for modifying various physiological or pathological processes. Furthermore, the development of selective calmodulin antagonists may provide a useful means for further studying the biological roles of calmodulin.


Phosphodiesterase Activity Cyclic Nucleotide Phosphodiesterase Calmodulin Antagonist Calmodulin Inhibitor Calmodulin Activity 
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  1. 1.
    Adunyah, E. S.; Niggli, V.; Carafoli, E. The anticalmodulin drugs trifluoperazine and R 24 571 remove the activation of the purified erythrocyte Ca2+ -ATPase by acidic phospholipids and by controlled proteolysisFEES Lett 143: 65–68, 1982.CrossRefGoogle Scholar
  2. 2.
    Blumenthal, D. K.; Stull, J. T. Activation of skeletal muscle myosin light chain kinase by calcium (2+) and calmodulinBiochemistry 19: 5608–5614, 1980.PubMedCrossRefGoogle Scholar
  3. 3.
    Brostrom, C. O.; Wolff, D. J. Properties and functions of calmodulinBiochem. Pharmacol 30: 1395–1405, 1981.PubMedCrossRefGoogle Scholar
  4. 4.
    Brostrom, S.-L.; Bengt, L.; Mardh, S.; Forsen, S.; Thulin, E. Interaction of the antihypertensive drug felodipine with calmodulinNature (London) 292: 777–778, 1981.CrossRefGoogle Scholar
  5. 5.
    Burgess, W. H. Characterization of calmodulin and calmodulin isotypes from sea urchin gametesJ. Biol. Chem 257: 1800–1804, 1982.PubMedGoogle Scholar
  6. 6.
    Chafouleas, J. G.; Dedman, J. R.; Munjaal, R. P.; Means, A. R. Calmodulin: Development and application of a sensitive radioimmunoassayJ. Biol. Chem 254: 10262–10267, 1979.PubMedGoogle Scholar
  7. 7.
    Chao, S. H.; Suzuki, Y.; Zysk, J. R.; Cheung, W. Y. Metal cation-induced activation of calmodulin is a function of ionic radiiFed. Proc 42: 1087, 1983.Google Scholar
  8. 8.
    Cheung, W. Y. Calmodulin plays a pivotal role in cellular regulationScience 207: 19–27, 1980.PubMedCrossRefGoogle Scholar
  9. 9.
    Comte, M.; Maulet, Y.; Cox, J. A. Ca2+ -dependent high-affinity complex formation between calmodulin and melittinBiochem. J 209: 269–272, 1983.PubMedGoogle Scholar
  10. 10.
    Cox, J. A.; Comte, M.; Stein, E. A. Activation of human erythrocyte Ca2+-dependent Mg2+-activated ATPase by calmodulin and calcium: Quantitative analysisProc. Natl. Acad. Sci. USA 79: 4265–4269, 1982.PubMedCrossRefGoogle Scholar
  11. 11.
    Cox, J. L.; Harrison, S. D. Correlation of metal toxicity with in vitro calmodulin inhibitionBiochem. Biophys. Res. Commun 115: 106–111, 1983.PubMedCrossRefGoogle Scholar
  12. 12.
    DeLorenzo, R. J.; Burdette, S.; Holderness, J. Benzodiazepine inhibition of the calcium-calmodulin protein kinase system in brain membraneScience 213: 546–549, 1981.PubMedCrossRefGoogle Scholar
  13. 13.
    Earl, C. Q.; Prozialeck, W. C.; Weiss, B. Interaction of alpha adrenergic antagonists with calmodulinLife Sci 35: 525–534, 1984.Google Scholar
  14. 14.
    Epstein, P. M.; Fiss, K.; Hachisu, R.; Andrenyak, D. M. Interaction of calcium antagonists with cyclic AMP phosphodiesterases and calmodulinBiochem. Biophys. Res. Commun 105: 1142–1149, 1982.PubMedCrossRefGoogle Scholar
  15. 15.
    Forsen, S.; Thulin, E.; Drakenberg, T.; Krebs, J.; Seamon, K. A 113Cd NMR study of calmodulin and its interaction with calcium, magnesium and trifluoperazineFEBS Lett 117: 189–194, 1980.PubMedCrossRefGoogle Scholar
  16. 16.
    Gietzen, K.; Delgado, E. S.; Bader, H. Compound 48/80: A powerful and specific inhibition of calmodulin- dependent Ca2+-transport ATPaseIRCS Med. Sci. Biochem 11: 12–13, 1983.Google Scholar
  17. 17.
    Gietzen, K.; Sadorf, I.; Bader, H. A model for the regulation of the calmodulin-dependent enzymes erythrocyte Ca2+-transport ATPase and brain phosphodiesterase by activators and inhibitorsBiochem.J 207: 541–548, 1982.PubMedGoogle Scholar
  18. 18.
    Hidaka, H.; Asano, M.; Tanaka, T. Activity-structure relationship of calmodulin antagonists: Naphthalenesulfonamide derivativesMol. Pharmacol 20: 571–578, 1981.PubMedGoogle Scholar
  19. 19.
    Hidaka, H.; Yamaki, T.; Naka, M.; Tanaka, T.; Hayashi, H.; Kobayashi, R. Calcium-regulated modulator protein interacting agents inhibit smooth muscle calcium-stimulated protein kinase and ATPaseMol. Pharmacol 17: 66–72, 1980.PubMedGoogle Scholar
  20. 20.
    Huang, C. Y.; Chau, V.; Chock, P. B.; Wang, J. H.; Sharma, R. K. Mechanism of activation of cyclic nucleotide phosphodiesterase: Requirement of the binding of four Ca2+ to calmodulin for activationProc. Natl. Acad. Sci. USA 78: 871–874, 1981.PubMedCrossRefGoogle Scholar
  21. 21.
    Kakiuchi, S.; Yasuda, S.; Yamazaki, R.; Teshima, Y.; Kanda, K.; Kakiuchi, R.; Sobue, K. Quantitative determinations of calmodulin in the supernatant and particulate fractions of mammalian tissuesJ. Biochem. (Tokyo) 92: 1041–1048, 1982.Google Scholar
  22. 22.
    Katoh, N.; Wise, B. C.; Wrenn, R. W.; Kuo, J. F. Inhibition by adriamycin of calmodulin-sensitive and phospholipid-sensitive calcium-dependent phosphorylation of endogenous proteins from heartBiochem. J 198: 199–205, 1981.PubMedGoogle Scholar
  23. 23.
    Kilimann, M.; Heilmeyer, L. M. G. The effect of Mg2 + on the Ca2 +-binding properties of non-activated phosphorylase kinaseEur. J. Biochem 73: 191–197, 1977.PubMedCrossRefGoogle Scholar
  24. 24.
    Klee, C. B. Calmodulin: Structure-function relationships. In: Calcium and Cell Function, volume 1, W. Y. Cheung, ed., New York, Academic Press, 1980, pp. 59–77.Google Scholar
  25. 25.
    Klee, C. B.; Crouch, T. H.; Richman, P. G. CalmodulinAnnu. Rev. Biochem 49: 489–515, 1980.PubMedCrossRefGoogle Scholar
  26. 26.
    Kurn, N. Inhibition of phosphate uptake by fluphenazine, a calmodulin inhibitor: Analysis of Volvox wild-type and fluphenazine resistant mutant strainsFEBS Lett 144: 68–72, 1982.PubMedCrossRefGoogle Scholar
  27. 27.
    Kurn, N.; Sela, B.-A. Altered calmodulin activity in fluphenazine-resistant mutant strains: Pleiotropic effect on development and cellular organization in Volvox carteriEur. J. Biochem 121: 53–57, 1981.PubMedCrossRefGoogle Scholar
  28. 28.
    Levin, R. M.; Weiss, B. Mechanism by which psychotropic drugs inhibit adenosine cyclic 3′, ′-monophosphate phosphodiesterase of brainMol. Pharmacol 12: 581–589, 1976.PubMedGoogle Scholar
  29. 29.
    Levin, R. M.; Weiss, B. Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesteraseMol. Pharmacol 13: 690–697, 1977.PubMedGoogle Scholar
  30. 30.
    Levin, R. M.; Weiss, B. Specificity of the binding of trifluoperazine to the calcium-dependent activator of phosphodiesterase and to a series of other calcium-binding proteinsBiochim. Biophys. Acta 540: 197–204, 1978.PubMedGoogle Scholar
  31. 31.
    Levin, R. M.; Weiss, B. Selective binding of antipsychotics and other psychoactive agents to the calcium- dependent activator of cyclic nucleotide-phosphodiesteraseJ. Pharmacol. Exp. Ther 208: 454–459, 1979.PubMedGoogle Scholar
  32. 32.
    Lin, Y. M.; Liu, Y. P.; Cheung, W. Y. Cyclic 3′:5′-nucleotide phosphodiesterase: Purification, characterization and active form of the protein activator from bovine brainJ. Biol. Chem 249: 4943–4954, 1974.PubMedGoogle Scholar
  33. 33.
    Luthra, M. G. Trifluoperazine inhibition of calmodulin-sensitive Ca2+-ATPase and calmodulin-insensitive (Na+ + K +)- and Mg2+-ATPase activities of human and rat red blood cellsBiochim. Biophys. Acta 692: 271–277, 1982.PubMedCrossRefGoogle Scholar
  34. 34.
    Malencik, D. A.; Anderson, S. R. Binding of hormones and neuropeptides by calmodulinBiochemistry 22: 1995–2001, 1983.PubMedCrossRefGoogle Scholar
  35. 35.
    Malnoe, A.; Cox, J. A.; Stein, E. A. Ca2+ -dependent regulation of calmodulin binding and adenylate cyclase activation in bovine cerebellar membranesBiochim. Biophys. Acta 714: 84–92, 1982.PubMedGoogle Scholar
  36. 36.
    Prozialeck, W. C. Structure-activity relationships of calmodulin antagonistsAnnu. Rep. Med. Chem 18: 203–212, 1983.CrossRefGoogle Scholar
  37. 37.
    Prozialeck, W. C.; Cimino, M.; Weiss, B. Photoaffinity labeling of calmodulin by phenothiazine antipsychoticsMol. Pharmacol 19: 264–269, 1981.PubMedGoogle Scholar
  38. 38.
    Prozialeck, W. C.; Wallace, T. L.; Weiss, B. Chlorpromazine-linked calmodulin: A novel calmodulin antagonistFed. Proc 42: 1087, 1983.Google Scholar
  39. 39.
    Prozialeck, W. C.; Weiss, B. Inhibition of calmodulin by phenothiazines and related drugs: Structure-activity relationshipsJ. Pharmacol. Exp. Ther 222: 509–516, 1982.PubMedGoogle Scholar
  40. 40.
    Roufogalis, B. D. Phenothiazine antagonism of calmodulin: A structurally-nonspecific interactionBiochem. Biophys. Res. Commun 98: 607–613, 1981.PubMedCrossRefGoogle Scholar
  41. 41.
    Seeman, P. Anti-schizophrenic drugs: Membrane receptor sites of actionBiochem. Pharmacol 26: 1741–1748, 1977.PubMedCrossRefGoogle Scholar
  42. 42.
    Sellinger-Barnette, M.; Weiss, B. Interaction of ß-endorphin and other opioid peptides with calmodulinMol. Pharmacol 21: 86–91, 1982.PubMedGoogle Scholar
  43. 43.
    Sellinger-Barnette, M.; Weiss, B. Interaction of various peptides with calmodulinAdv. Cyclic Nucleotide Protein Phosphorylation Res 16: 261–276, 1984.PubMedGoogle Scholar
  44. 44.
    Sharma, R. K.; Wang, J. H. Inhibition of calmodulin-activated cyclic nucleotide phosphodiesterase by Triton X-100Biochem. Biophys. Res. Commun 100: 710–715, 1981.PubMedCrossRefGoogle Scholar
  45. 45.
    Shimizu, T.; Hatano, M.; Nagao, S.; Nozawa, Y. 43Ca NMR studies of Ca2 + -Tetrahymena calmodulin complexesBiochem. Biophys. Res. Commun 106: 1112–1118, 1982.PubMedCrossRefGoogle Scholar
  46. 46.
    Tanaka, T.; Hidaka, H. Interaction of local anesthetics with calmodulinBiochem. Biophys. Res. Commun 101: 447–453, 1981.PubMedCrossRefGoogle Scholar
  47. 47.
    Teo, T. S.; Wang, J. H. Mechanism of activation of a cyclic adenosine 3′:5′ monophosphate phosphodiesterase from bovine heart by Ca2+ ionsJ. Biol. Chem 248: 5950–5955, 1973.PubMedGoogle Scholar
  48. 48.
    Van Belle, H. R 24 571: A potent inhibitor of calmodulin-activated enzymesCell Calcium 2: 483–494, 1981.CrossRefGoogle Scholar
  49. 49.
    Volpi, M.; Sha’afi, R. I.; Epstein, P. M.; Andrenyak, D. M.; Feinstein, M. B. Local anesthetics, mepacrine and propranolol are antagonists of calmodulinProc. Natl. Acad. Sci. USA 78: 795–799, 1981.PubMedCrossRefGoogle Scholar
  50. 50.
    Volpi, M.; Sha’afi, R. I.; Feinstein, M. B. Antagonism of calmodulin by local anesthetics: Inhibition of calmodulin-stimulated calcium transport of inside-out membrane vesiclesMol. Pharmacol 20: 363–370, 1981.PubMedGoogle Scholar
  51. 51.
    Watanabe, K.; West, W. L. Calmodulin, activated cyclic nucleotide phosphodiesterase, microtubules, and vinca alkaloidsFed. Proc 41: 2292–2299, 1982.PubMedGoogle Scholar
  52. 52.
    Watanabe, K.; Williams, E. F.; Law, J. S.; West, W. L. Effects of vinca alkaloids on calcium-calmodulin regulated cyclic adenosine 3′,5′-monophosphate phosphodiesterase activity from brainBiochem. Pharmacol 30: 335–340, 1981.PubMedCrossRefGoogle Scholar
  53. 53.
    Weiss, B. Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesteraseAdv. Cyclic Nucleotide Res 5: 195–211, 1975.PubMedGoogle Scholar
  54. 54.
    Weiss, B.; Fertel, R.; Figlin, R.; Uzunov, P. Selective alteration of the activity of the multiple forms of adenosine 3′,5′-monophosphate phosphodiesterase of rat cerebrumMol. Pharmacol 10: 615–625, 1974.Google Scholar
  55. 55.
    Weiss, B.; Hait, W. N. Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agentsAnnu. Rev. Pharmacol. Toxicol 17: 441–477, 1977.PubMedCrossRefGoogle Scholar
  56. 56.
    Weiss, B.; Prozialeck, W. C.; Cimino, M.; Barnette, M. S.; Wallace, T. L. Pharmacological regulation of calmodulinAnn. N.Y. Acad. Sci 356: 319–345, 1980.PubMedCrossRefGoogle Scholar
  57. 57.
    Weiss, B.; Prozialeck, W. C.; Wallace, T. L. Interaction of drugs with calmodulin: Biochemical, pharmacological and clinical implicationsBiochem. Pharmacol 31: 2217–2226, 1982.PubMedCrossRefGoogle Scholar
  58. 58.
    Weiss, B.; Sellinger-Barnette, M. Effects of antipsychotic dopamine antagonists and polypeptide hormones on calmodulin. In: Apomorphine and Other Dopaminomimetics, Volume 1, G. L. Gessa and G. U. Corsini, eds., New York, Raven Press, 1981, pp. 179–192.Google Scholar
  59. 59.
    Weiss, B.; Wallace, T. L. Mechanisms and pharmacological implications of altering calmodulin activity. In: Calcium and Cell Function, Volume 1, W. Y. Cheung, ed., New York, Academic Press, 1980, pp. 329–379.Google Scholar
  60. 60.
    Zavecz, J. H.; Jackson, T. E.; Limp, G. L.; Yellin, T. O. Relationship between anti-diarrheal activity and binding to calmodulinEur. J. Pharmacol 78: 375–377, 1982.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Walter C. Prozialeck
    • 1
  • Benjamin Weiss
    • 2
  1. 1.Department of Physiology and PharmacologyPhiladelphia College of Osteopathic MedicinePhiladelphiaUSA
  2. 2.Department of PharmacologyMedical College of PennsylvaniaPhiladelphiaUSA

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