Download PDF
Thromb Haemost 1978; 40(02): 232-240
DOI: 10.1055/s-0038-1648657
VIth International Congress on Thrombosis and Haemostasis
Schattauer GmbH Stuttgart

Cyclic Nucleotides in Platelet Function[*]

R J Haslam
The Department of Pathology, McMaster University Hamilton, Ontario, Canada L8S 4J9
,
M M L Davidson
The Department of Pathology, McMaster University Hamilton, Ontario, Canada L8S 4J9
,
J E B Fox
The Department of Pathology, McMaster University Hamilton, Ontario, Canada L8S 4J9
,
J A Lynham
The Department of Pathology, McMaster University Hamilton, Ontario, Canada L8S 4J9
› Author Affiliations
Further Information

Publication History

Publication Date:
12 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Inhibition of adenylate cyclase in intact platelets by addition of compounds such as 2’, 5’- dideoxyadenosine prevented the inhibition of platelet aggregation by PGE1 but did not affect the responses of platelets to aggregating agents in the absence of PGE1. This confirms that cyclic AMP mediates the effects of PGE1 but indicates that the level of cyclic AMP in unstimulated platelets is too low to affect the actions of aggregating agents. Studies on the phosphorylation of proteins in intact 32P-labelled platelets showed that PGE1 increased the phosphorylation of a membrane-bound polypeptide (P24) and prevented the increased phosphorylation of other polypeptides (P47 and P20) that occurred on addition of inducers of the release reaction. It is suggested that the cyclic AMP-dependent phosphorylation of P24 stimulates the active transport of Ca2+ out of the platelet cytosol, so preventing phosphorylation of P47 and P20, reactions which may be involved in the release mechanism. As increases in platelet cyclic GMP could be dissociated from both platelet aggregation and the release reaction, it is proposed that the bidirectional regulation of platelet function is achieved primarily by the opposing actions of increases in the concentrations of Ca2+ and cyclic AMP.

* Invited Symposium V “Platelets: Intravascular Control Mechanisms” presented to VIth International Congress on Thrombosis and Haemostasis, philadelphia, U. S. A. June 1977.


 

  • References

  • 1 Ball G, Brereton GG, Fulwood M, Ireland DM, Yates P. 1970; Effect of prostaglandin E1alone and in combination with theophylline or aspirin on collagen-induced platelet aggregation and on platelet nucleotides including adenosine 3’:5’-cyclic monophosphate. Biochemical Journal 120: 709
    CrossrefPubMedGoogle Scholar
  • 2 Berridge MJ. 1975. The interaction of cyclic nucleotides and calcium in the control of cellular activity. In: GREENGARD P, ROBISON GA. (eds.) Advances in Cyclic Nucleotide Research, Raven Press; NewYork: vol. 6 p 1
    Google Scholar
  • 3 Booyse FM, Marr J, Yang DC, Guiliani D, Rafelson ME. 1976; Adenosine cyclic 3’,5’-monophosphate-dependent protein kinase from human platelets. Biochimica et Biophysica Acta 422: 60
    CrossrefPubMedGoogle Scholar
  • 4 Charo IF, Feinman RD, Detwiler TC. 1976; Inhibition of platelet secretion by an antagonist of intracellular calcium. Biochemical and Biophysical Research Communications 72: 1462
    CrossrefPubMedGoogle Scholar
  • 5 Chiang TM, Dixit SN, Kang AH. 1976; Effect of cyclic 3’,5’-guanosine monophosphate on human platelet function. Journal of Laboratory and Clinical Medicine 88: 215
    PubMedGoogle Scholar
  • 6 Claesson HE, Malmsten C. 1977; On the interrelationship of prostaglandin endoperoxide G2 and cyclic nucleotides in platelet function. European Journal of Biochemistry 76: 277
    CrossrefPubMedGoogle Scholar
  • 7 Cole B, Robison GA, Hartmann RC. 1971; Studies on the role of cyclic AMP in platelet function. Annals of the New York Academy of Sciences 185: 477
    CrossrefPubMedGoogle Scholar
  • 8 Daniel JL, Holmsen H, Adelstein RS. 1977; Thrombin stimulated myosin phosphorylation in intact platelets and its possible involvement in secretion. Thrombosis and Haemostasis 38: 984
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Davies T, Davidson MM L, Mcclenaghan MD, Say A, Haslam RJ. 1976; Factors affecting platelet cyclic GMP levels during aggregation induced by collagen and by arachidonic acid. Thrombosis Research 9: 387
    CrossrefPubMedGoogle Scholar
  • 10 Fain JN, Pointer RH, Ward WF. 1972; Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. Journal of Biological Chemistry 247: 6866
    PubMedGoogle Scholar
  • 11 Feinman RD, Detwiler TC. 1974; Platelet secretion induced by divalent cation ionophores. Nature 249: 172
    CrossrefPubMedGoogle Scholar
  • 12 Feinstein MB, Fiekers J, Fraser C. 1976; An analysis of the mechanism of local anaesthetic inhibition of platelet aggregation and secretion. Journal of Pharmacology and Experimental Therapeutics 197: 215
    PubMedGoogle Scholar
  • 13 Fox JE B, Lynham JA, Haslam RJ. 1978; Phosphorylation of human platelet proteins by agents that induce or inhibit the platelet release reaction. Federation Proceedings 37: 799
    PubMedGoogle Scholar
  • 14 Glusa E, Markwardt F, Stürzebecher J. 1974; Effects of sodium nitroprusside and other pentacyanonitrosyl complexes on platelet aggregation. Haemostasis 3: 249
    PubMedGoogle Scholar
  • 15 Goldberg ND, Haddox MK, Estensen R, White JG, Lopez C, Hadden JW. 1974. Evidence of a dualism between cyclic GMP and cyclic AMP in the regulation of cell proliferation and other cellular processes. In: Braun W, Lichtenstein L, Parker C. (eds.) Cyclic AMP, Cell Growth and the Immune Response. Springer-Verlag; NewYork: p 247
    Google Scholar
  • 16 Goldberg ND, Haddox MK, Nicol SE, Glass DB, Sanford CH, Kuehl FA, Estensen R. 1975. Biologic regulation through opposing influences of cyclic GMP and cyclic AMP: the yin-yang hypothesis. In: Drummond GI, Greengard P, Robison GA. (eds.) Advances in Cyclic Nucleotide Researc. Raven Press; NewYork: vol. 5 p 307
    Google Scholar
  • 17 Harris DN, Phillips MB, Goldenberg HJ. 1975; Effect of substituted purines on the inhibition by PGEj of ADP-induced aggregation of human platelets and on the increase in cyclic AMP induced in platelets by PGE1 . Federation Proceedings 34: 617
    PubMedGoogle Scholar
  • 18 Haslam RJ. 1975. Roles of cyclic nucleotides in platelet function. In: Biochemistry and Pharmacology of Platelets. Ciba Foundation Symposium 35 (new series) Elsevier/Excerpta Medica/ North-Holland; Amsterdam: p 121
    Google Scholar
  • 19 Haslam RJ. 1978. Cyclic nucleotides in platelet function. In: DAY HJ, Holmsen H, Zucker MB. (eds.) Platelet Function Testing, Proceedings from Workshop on Platelets. Philadelphia; 18.10.1976. U.S. Department of Health, Education and Welfare, DHEW Publication No.(NIH); 78-1087 p 487
    Google Scholar
  • 20 Haslam RJ, Davidson MM L, Davies T, Lynham JA, Mcclenaghan MD. 1978. Regulation of blood platelet function by cyclic nucleotides. In George WJ, Ignarro LJ. (eds.) Advances in Cyclic Nucleotide Research. Raven Press; NewYork: vol. 9 p 533
    Google Scholar
  • 21 Haslam RJ, Davidson MM L, Desiardins JV. 1977; Role of cyclic AMP in platelet function: evidence from inhibition of adenylate cyclase in intact platelets by adenosine analogues. Thrombosis and Haemostasis 38: 6
    PubMedGoogle Scholar
  • 22 Haslam RJ, Lynham JA. 1976; Increased phosphorylation of specific blood platelet proteins in association with the release reaction. Biochemical Society Transactions 4: 694
    CrossrefPubMedGoogle Scholar
  • 23 Haslam RJ, Lynham JA. 1977; Relationship between phosphorylation of blood platelet proteins and secretion of platelet granule constituents I. Effects of different aggregating agents. Biochemical and Biophysical Research Communications 77: 714
    CrossrefPubMedGoogle Scholar
  • 24 Haslam RJ, Mcclenaghan MD. 1974; Effects of collagen and of aspirin on the concentration of guanosine 3’:5’-cyclic monophosphate in human blood platelets: measurement by a prelabelling technique. Biochemical Journal 138: 317
    CrossrefPubMedGoogle Scholar
  • 25 Haslam RJ, Rosson GM. 1975; Effects of adenosine on levels of adenosine cyclic 3’,5’- monophosphate in human blood platelets in relation to adenosine incorporation and platelet aggregation. Molecular Pharmacology 11: 528
    PubMedGoogle Scholar
  • 26 Haslam RJ, Taylor A. 1971. Role of cyclic 3’,5’-adenosine monophosphate in platelet aggregation. In: Caen J. (ed.) Platelet Aggregation. Masson & Cie; Paris: p 85
    Google Scholar
  • 27 Käser-Glanzmann R, Jakíbová M, George JN, Lücher EF. 1977; Stimulation of calcium uptake in platelet membrane vesicles by adenosine 3’,5’-cyclic monophosphate and protein kinase. Biochimica et Biophysica Acta 466: 429
    CrossrefPubMedGoogle Scholar
  • 28 Laemmli UK. 1970; Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680
    CrossrefPubMedGoogle Scholar
  • 29 Le Breton GC, Dinerstein RJ, Roth LJ, Feinberg H. 1976; Direct evidence for intracellular divalent cation redistribution associated with platelet shape change. Biochemical and Biophysical Research Communications 71: 362
    CrossrefPubMedGoogle Scholar
  • 30 Lyons RM, Stanford N, Majerus PW. 1975; Thrombin-induced protein phosphorylation in human platelets. Journal of Clinical Investigation 56: 924
    CrossrefPubMedGoogle Scholar
  • 31 Marquis NR, Becker JA, Vigdahl RL. 1970; Platelet aggregation III. An epinephrine induced decrease in cyclic AMP synthesis. Biochemical and Biophysical Research Communications 39: 783
    CrossrefPubMedGoogle Scholar
  • 32 Marquis NR, Vigdahl RL, Tavormina PA. 1969; Platelet aggregation. I. Regulation by cyclic AMP and prostaglandin E1 . Biochemical and Biophysical Research Communications 36: 965
    CrossrefPubMedGoogle Scholar
  • 33 Minkes M, Stanford N, Chi MM Y, Roth GJ, Raz A, Needleman P, Majerus PW. 1977; Cyclic adenosine 3’,5’-monophosphate inhibits the availability of arachidonate to prostaglandin synthetase in human platelet suspensions. Journal of Clinical Investigation 59: 449
    CrossrefPubMedGoogle Scholar
  • 34 Robison GA, Arnold A, Hartmann RC. 1969; Divergent effects of epinephrine and prostaglandin E1on the level of cyclic AMP in human blood platelets. Pharmacological Research Communications 1: 325
    CrossrefPubMedGoogle Scholar
  • 35 Robison GA, Butcher RW, Sutherland EW. 1967; Adenyl cyclase as an adrenergic receptor. Annals of the NewYork Academy of Sciences 139: 703
    PubMedGoogle Scholar
  • 36 Salzman EW. 1972; Cyclic AMP and platelet function. New England Journal of Medicine 286: 358
    CrossrefPubMedGoogle Scholar
  • 37 Salzman EW, Macintyre DE, Gordon JL, Steer M. 1977; Enhancement of platelet activity by inhibition of adenylate cyclase. Thrombosis and Haemostasis 38: 6
    PubMedGoogle Scholar
  • 38 Schoepflin GS, Pickett W, Austen KF, Goetzl EJ. 1977; Elevation of the cyclic GMP concentration in human platelets by sodium ascorbate and 5-hydroxytryptamine. Journal of Cyclic Nucleotide Research 3: 355
    PubMedGoogle Scholar
  • 39 Schultz KD, Schultz K, Schultz G. 1977; Sodium nitroprusside and other smooth muscle- relaxants increase cyclic GMP levels in rat ductus deferens. Nature 265: 750
    CrossrefPubMedGoogle Scholar
  • 40 Steiner M. 1975; Endogenous phosphorylation of platelet membrane proteins. Archives of Biochemistry and Biophysics 171: 245
    CrossrefPubMedGoogle Scholar
  • 41 Sutherland EW, Robison GA, Butcher RW. 1968; Some aspects of the biological role of adenosine 3’,5’-monophosphate (cyclic AMP). Circulation 37: 279
    CrossrefPubMedGoogle Scholar
  • 42 Tada M, Kirchberger MA, Katz AM. 1975; Phosphorylation of a 22,000 dalton component of the sarcoplasmic reticulum by adenosine 3’,5’-monophosphate-dependent protein kinase. Journal of Biological Chemistry 250: 2640
    PubMedGoogle Scholar
  • 43 Weinryb I, Michel IM. 1974; Potent magnesium-dependent inhibition of adenylate cyclase activity from guinea pig lung by adenosine and other 9-substituted adenines. Biochimica et Biophysica Acta 334: 218
    CrossrefPubMedGoogle Scholar
  • 44 Wolfe SM, Shulman NR. 1969; Adenyl cyclase activity in human platelets. Biochemical and Biophysical Research Communications 35: 265
    CrossrefPubMedGoogle Scholar