Roles of Cyclic Nucleotides in Platelet Function

2008 ◽  
pp. 121-151 ◽  
Author(s):  
Richard J. Haslam
Keyword(s):  
Platelet Function ◽  
Cyclic Nucleotides

AN EVALUATION OF THE ROLE OF CYCLIC NUCLEOTIDES IN PLATELET FUNCTION

Abstracts ◽  
1978 ◽  
pp. 720
Author(s):  
L.C. Best ◽  
T.K. Holland ◽  
M.B. McGuire ◽  
T.J. Martin ◽  
R.G.G. Russell
Keyword(s):  
Platelet Function ◽  
Cyclic Nucleotides

Cyclic Nucleotides and Phosphodiesterases in Platelets

1999 ◽  
Vol 82 (08) ◽  
pp. 412-423 ◽  
Author(s):  
Natalie Dickinson ◽  
Elliott Jang ◽  
Richard Haslam
Keyword(s):  
Nitric Oxide ◽  
Platelet Aggregation ◽  
Adenylyl Cyclase ◽  
Protein Kinases ◽  
Platelet Function ◽  
Cyclic Nucleotides ◽  
Antithrombotic Agents ◽  
Dependent Protein ◽  
Camp And Cgmp ◽  
Camp Formation

IntroductionIt is now almost 30 years since the discovery that prostaglandin E1 (PGE1) inhibits platelet responses to aggregating agents, together with finding that the effects of this compound are mediated by adenosine 3′, 5′-cyclic monophosphate (cAMP) initiated interest in the physiological and pharmacological regulation of platelet function by other agents that increase platelet cAMP, as reviewed elsewhere.1 The most important agonists that stimulate cAMP formation in platelets have now been identified as prostacyclin (PGI2), prostaglandin D2 (PGD2), and adenosine, which exert their effects through receptors of the serpentine or seven transmembrane segment class (IP, DP and A2 receptors, respectively).2 The latter then stimulate cAMP formation by adenylyl cyclase via the GTP-dependent activation of the G-protein, Gs (Fig. 1). In the classical view, cAMP exerts its effects solely by binding to the RI and RII regulatory subunits of type I and type II cAMP-dependent protein kinases (PKA). The catalytic subunits of the kinases then dissociate and phosphorylate selected serine and threonine residues on target proteins that prevent or reverse platelet activation.2 A crucial role is played by cAMP phosphodiesterases, which degrade cAMP to 5′-AMP, thereby diminishing and terminating the effects of agonists that stimulate cAMP formation (Fig. 1). In early studies, this was demonstrated by the ability of first-generation inhibitors of cAMP phosphodiesterases, particularly the methylxanthines, to inhibit platelet aggregation and potentiate the inhibitory effects of activators of platelet adenylyl cyclase.1 Such studies provided the rationale for the subsequent development of more potent and selective phosphodiesterase inhibitors as potential antithrombotic agents.Interest in the role of guanosine 3′,5′-cyclic monophosphate (cGMP) in platelets closely followed the discovery of the inhibitory action of cAMP. An early hypothesis that cGMP might potentiate platelet aggregation was abandoned by 1978, after it was shown that some inhibitors of platelet aggregation, such as nitroprusside (NP), also increased platelet cGMP.1 It soon emerged that all nitrovasodilators release nitric oxide and activate soluble guanylyl cyclase (GC) and that the cGMP formed stimulates cGMP-dependent protein kinases (PKG) in many cells and tissues (Fig. 1), including vascular smooth muscle and platelets.3 The crucial physiological importance of this pathway was established with the identification of endothelium-derived relaxing factor (EDRF) as nitric oxide.4 cGMP phosphodiesterases play an essential role by limiting increases in cellular cGMP, and inhibition of these enzymes was found to potentiate the effects of nitric oxide and nitric oxide donors on platelets and other cells.5 The ability of cAMP and cGMP to activate distinct protein kinases led to a persistent view that these two cyclic nucleotides operate in parallel and independent ways to inhibit platelet function, cAMP mediating the effects of agonists such as PGI2, and cGMP mediating the effects of nitric oxide.2,3 However, over the last 10 years, considerable evidence has accumulated to indicate that this is not the case in platelets (or in many other cells) and that cross-talk between the cAMP and cGMP systems may occur on at least two levels, affecting both cyclic nucleotide phosphodiesterase (PDE) and protein kinase activities (Fig. 1). One of the most significant of these interactions is through the effects of cGMP on the hydrolysis of cAMP by PDEs. It is the purpose of this chapter to describe platelet PDEs and to discuss how their individual characteristics and regulation may impact platelet function and the design of useful antithrombotic agents. In addition, evidence that both cGMP and cAMP may activate PKG and that these cyclic nucleotides may exert effects in platelets that do not involve either PKA or PKG will be discussed briefly.

Cyclic Nucleotides in Platelet Function

1978 ◽  
Vol 40 (02) ◽  
pp. 232-240 ◽  
Author(s):  
R J Haslam ◽  
M M L Davidson ◽  
J E B Fox ◽  
J A Lynham
Keyword(s):  
Platelet Aggregation ◽  
Cyclic Amp ◽  
Platelet Function ◽  
Cyclic Nucleotides ◽  
Release Mechanism ◽  
Release Reaction ◽  
Phosphorylation Of Proteins ◽  
Inhibition Of Platelet Aggregation ◽  
Bidirectional Regulation ◽  
Membrane Bound

SummaryInhibition 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.

EFFECT OF ATRIAL NATRIURETIC POLYPEPTIDES ON PLATELET FUNCTION

1987 ◽  
Author(s):  
T Asaji ◽  
E Murakami ◽  
N Takekoshi ◽  
S Matsui ◽  
T Imaoka
Keyword(s):  
Protein Phosphorylation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Cyclic Nucleotides ◽  
Human Platelet ◽  
Early Stage ◽  
Platelet Rich Plasma ◽  
Heart Insufficiency ◽  
32P Incorporation ◽  
Atrial Natriuretic

Atrial natriuretic polypeptides (ANP) have been shown to possess a potent diuretic and natriuretic activity, and medicated to patients with heart insufficiency as a drug to be mediated by cGMPaccumulation in glomeruli. A existence of receptors for ANP have recently beenreported in human platelet. But, whether ANP has a direct effect on platelet function remains to be known.Single stimulation of ANP in any concentration did not induce aggregation in neither platelet rich plasma, nor washed platelets. Also no effect of pretreatment with ANP was observed against aggregation triggered by known mediators of platelet activation (Thrombin, ADP, Epinephrine, Collagen) using platelet rich plasma and washed platelets.Therefore, biochemical parameters such as cyclic nucleotides (cAMP, cGMP), phosphatidylinositol hydrolysis and protein phosphorylation, leading to the early stage of platelet activation were examined to investigate the effect of ANP in receptor linked transducing mechanism. Neither cyclic nucleotides accumulation nor [32 P] phosphatidic acid production were detected in platelets treated with ANP. ANP caused a small increase of 32P incorporation into M 30K protein, but no change on the level of phosphorylation of 47K, 20K protein (Imaoka, T. and Haslam, R.J., J.Biol.Chem.258,11404, 1983) was observed.These results clearly suggested thatANP binding with membrane receptor was not linked with adenylate cyclase, ganulate cyclase and phosphatidylinositol phosphate turnover in human platelet, maybe because of too few numbers of ANP receptor. Mechanism of 30K protein phosphorylation and Ca++ mobilization are important subjects for future study, (supported by MESC of Japan)

Roles Of Cyclic Nucleotides In The Inhibition Of Platelet Function By Nitroprusside And By Ascorbate

1981 ◽  
Author(s):  
M M L Davidson ◽  
R J Haslam
Keyword(s):  
Cyclic Amp ◽  
Adenylate Cyclase ◽  
Platelet Function ◽  
Cyclic Gmp ◽  
Cyclic Nucleotides ◽  
Human Platelets ◽  
Dense Granule ◽  
Inhibitory Effects ◽  
Maximum Value ◽  
Induced Aggregation

The effects of nitroprusside and of ascorbate on the collagen-induced aggregation of washed human platelets and on the associated release of dense granule constituents were correlated with their effects on platelet cyclic GMP and cyclic AMP, which were measured either by radioimmunoassays or prelabelling methods. Nitroprusside at concentrations from 1 to 400 μM increased platelet cyclic GMP from 6 to 100-fold (maximum value approx. 50 pmol/109 platelets) and at concentrations above 10 μM also increased cyclic AMP about 2-fold (maximum value approx. 36 pmol/109 platelets). Platelet cyclic GMP reached a peak after an incubation period inversely related to the nitroprusside concentration and then declined. Collagen, which increased platelet cyclic GMP about 2-fold, enhanced the effect of nitroprusside on cyclic GMP but not cyclic AMP. Freshly prepared ascorbate (10 mM) increased platelet cyclic GMP about 8-fold. Storage of the ascorbate at pH 7 or simultaneous addition of 5 μM CuCl2 potentiated its action to give 15 to 20-fold increases in cyclic GMP and small increases in cyclic AMP. The results suggested that oxidation of the ascorbate was involved in these effects. In all the above studies, increases in platelet cyclic GMP greater than 6 to 10-fold were associated with measurable increases in cyclic AMP and with inhibitions of collagen-induced platelet responses that roughly correlated with the cyclic nucleotide changes. Addition of 100 μM 2',5'-dideoxyadenosine (an inhibitor of adenylate cyclase) blocked increases in platelet cyclic AMP but did not affect increases in cyclic GMP; this compound also decreased (but did not abolish) the inhibitory effects of nitroprusside and of ascorbate + CuCl2 These findings suggested roles for both cyclic GMP and cyclic AMP in mediating the inhibitions of platelet function by nitroprusside and ascorbate.

Negative regulation of platelet function by a secreted cell repulsive protein, semaphorin 3A

Blood ◽  
2005 ◽  
Vol 106 (3) ◽  
pp. 913-921 ◽  
Author(s):  
Hirokazu Kashiwagi ◽  
Masamichi Shiraga ◽  
Hisashi Kato ◽  
Tsuyoshi Kamae ◽  
Naoko Yamamoto ◽  
...  
Keyword(s):  
Platelet Function ◽  
Cyclic Nucleotides ◽  
Platelet Adhesion ◽  
Axon Growth ◽  
Adenosine Diphosphate ◽  
Negative Regulation ◽  
Semaphorin 3A ◽  
Growth Cone Collapse ◽  
Dose Dependent ◽  
Actin Rearrangement

AbstractSemaphorin 3A (Sema3A) is a secreted disulfide-bound homodimeric molecule that induces growth cone collapse and repulsion of axon growth in the nervous system. Recently, it has been demonstrated that Sema3A is produced by endothelial cells and inhibits integrin function in an autocrine fashion. In this study, we investigated the effects of Sema3A on platelet function by using 2 distinct human Sema3A chimera proteins. We detected expression of functional Sema3A receptors in platelets and dose-dependent and saturable binding of Sema3A to platelets. Sema3A dose-dependently inhibited activation of integrin αIIbβ3byall agonists examined including adenosine diphosphate (ADP), thrombin, convulxin, phorbol 12-myristate 13-acetate, and A23187. Sema3A inhibited not only platelet aggregation induced by thrombin or collagen but also platelet adhesion and spreading on immobilized fibrinogen. Moreover, Sema3A impaired αIIbβ3-independent spreading on glass coverslips and aggregation-independent granular secretion. Sema3A inhibited agonist-induced elevation of filamentous action (F-actin) contents, phosphorylation of cofilin, and Rac1 activation. In contrast, Sema3A did not affect the levels of cyclic nucleotides or agonist-induced increase of intracellular Ca2+ concentrations. Thus, the extensive inhibition of platelet function by Sema3A appears to be mediated, at least in part, through impairment of agonist-induced Rac1-dependent actin rearrangement.

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