The Role of The Phosphoinositide-Derived Second Messenger Molecules in Platelet Activation

Our knowledge on the expression, regulation and roles of the different phosphoinositide 3-kinases (PI3Ks) in platelet signaling and functions has greatly expanded these last twenty years. Much progress has been made in understanding the roles and regulations of class I PI3Ks which produce the lipid second messenger phosphatidylinositol 3,4,5 trisphosphate (PtdIns(3,4,5)P3). Selective pharmacological inhibitors and genetic approaches have allowed researchers to generate an impressive amount of data on the role of class I PI3Kα, β, δ and γ in platelet activation and in thrombosis. Furthermore, platelets do also express two class II PI3Ks (PI3KC2α and PI3KC2β), thought to generate PtdIns(3,4)P2 and PtdIns3P, and the sole class III PI3K (Vps34), known to synthesize PtdIns3P. Recent studies have started to reveal the importance of PI3KC2α and Vps34 in megakaryocytes and platelets, opening new perspective in our comprehension of platelet biology and thrombosis. In this review, we will summarize previous and recent advances on platelet PI3Ks isoforms. The implication of these kinases and their lipid products in fundamental platelet biological processes and thrombosis will be discussed. Finally, the relevance of developing potential antithrombotic strategies by targeting PI3Ks will be examined.

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On The Mechanism Of Heparin-Induced Potentiation Of Platelet Aggregation

10.1055/s-0038-1652598 ◽

1981 ◽

Author(s):

M Yamamoto ◽

K Watanabe ◽

Y Ando ◽

H Iri ◽

N Fujiyama ◽

...

Keyword(s):

Platelet Aggregation ◽

Platelet Activation ◽

Coagulation Factors ◽

Marked Enhancement ◽

Matrix Bound ◽

Induced Aggregation ◽

Aggregation Of Platelets ◽

Plasma Heparin

It has been suggested that heparin caused potentiation of aggregation induced by ADP or epinephrine. The exact mechanism of heparin-induced platelet activation, however, remained unknown. In this paper, we have investigated the role of anti-thrombin III ( AT ) in heparin-induced platelet activation using purified AT and AT depleted plasma. When ADP or epinephrine was added to citrated PRP one minute after addition of heparin ( 1 u/ml, porcine intestinal mucosal heparin, Sigma Co. USA ), marked enhancement of platelet aggregation was observed, compared with the degree of aggregation in the absence of heparin. However, in platelet suspensions prepared in modified Tyrode’s solution, heparin exhibited no potentiating effect on platelet aggregation induced by epinephrine or ADP. Potentiation of epinephrine- or ADP-induced platelet aggregation by heparin was demonstrated when purified AT was added to platelet suspensions at a concentration of 20 μg/ml. AT depleted plasma, which was prepared by immunosorption using matrix-bound antibodies to AT, retained no AT, while determination of α1-antitrypsinα2- macroglobulin and fibrinogen in AT depleted plasma produced values which corresponded to those of the original plasma when dilution factor was taken into account. The activities of coagulation factors were also comparable to those of the original plasma. Heparin exhibited potentiating effect on ADP- or epinephrine-induced aggregation of platelets in original plasma, but no effect in AT depleted plasma. When purified AT was added back to AT depleted plasma at a concentration of 20 μg/ml, potentiation of platelet aggregation by heparin was clearly demonstrated.Our results suggest that effect of heparin on platelet aggregation is also mediated by anti-thrombin III.

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Role of Calcium in Platelet Activation: Novel Insights and Pharmacological Implications

Medicinal Chemistry ◽

10.2174/157340641202160208195923 ◽

2016 ◽

Vol 12 (2) ◽

pp. 131-138 ◽

Cited By ~ 9

Author(s):

Periklis Davlouros ◽

Ioanna Xanthopoulou ◽

Nikolaos Mparampoutis ◽

Georgios Giannopoulos ◽

Spyridon Deftereos ◽

...

Keyword(s):

Platelet Activation

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A role of calcium-activated phospholipid-dependent protein kinase in human platelet activation. Comparison of thrombin and collagen actions.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)33089-8 ◽

1983 ◽

Vol 258 (3) ◽

pp. 2010-2013 ◽

Cited By ~ 24

Author(s):

K Sano ◽

Y Takai ◽

J Yamanishi ◽

Y Nishizuka

Keyword(s):

Protein Kinase ◽

Platelet Activation ◽

Human Platelet ◽

Dependent Protein Kinase ◽

Dependent Protein

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Lipopolysaccharide induces platelet activation in HIV patients: the role of different viral load patterns

HIV Medicine ◽

10.1111/hiv.13059 ◽

2021 ◽

Author(s):

Cristina Nocella ◽

Ivano Mezzaroma ◽

Vittoria Cammisotto ◽

Valentina Castellani ◽

Cinzia Milito ◽

...

Keyword(s):

Viral Load ◽

Platelet Activation ◽

Hiv Patients

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The Role of Endogenously Formed Diacylglycerol in the Propagation and Termination of Platelet Activation

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)94063-9 ◽

1989 ◽

Vol 264 (6) ◽

pp. 3274-3285 ◽

Cited By ~ 4

Author(s):

D de Chaffoy de Courcelles ◽

P Roevens ◽

H Van Belle ◽

L Kennis ◽

Y Somers ◽

...

Keyword(s):

Platelet Activation

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The (Patho)Biology of SRC Kinase in Platelets and Megakaryocytes

Medicina ◽

10.3390/medicina56120633 ◽

2020 ◽

Vol 56 (12) ◽

pp. 633

Author(s):

Lore De Kock ◽

Kathleen Freson

Keyword(s):

Platelet Activation ◽

Knockout Mice ◽

Missense Variant ◽

Surface Receptors ◽

Src Signaling ◽

Normal Platelet ◽

Fibrinogen Binding ◽

Cellular Environment ◽

Proplatelet Formation

Proto-oncogene tyrosine-protein kinase SRC (SRC), as other members of the SRC family kinases (SFK), plays an important role in regulating signal transduction by different cell surface receptors after changes in the cellular environment. Here, we reviewed the role of SRC in platelets and megakaryocytes (MK). In platelets, inactive closed SRC is coupled to the β subunit of integrin αIIbβ3 while upon fibrinogen binding during platelet activation, αIIbβ3-mediated outside-in signaling is initiated by activation of SRC. Active open SRC now further stimulates many downstream effectors via tyrosine phosphorylation of enzymes, adaptors, and especially cytoskeletal components. Functional platelet studies using SRC knockout mice or broad spectrum SFK inhibitors pointed out that SRC mediates their spreading on fibrinogen. On the other hand, an activating pathological SRC missense variant E527K in humans that causes bleeding inhibits collagen-induced platelet activation while stimulating platelet spreading. The role of SRC in megakaryopoiesis is much less studied. SRC knockout mice have a normal platelet count though studies with SFK inhibitors point out that SRC could interfere with MK polyploidization and proplatelet formation but these inhibitors are not specific. Patients with the SRC E527K variant have thrombocytopenia due to hyperactive SRC that inhibits proplatelet formation after increased spreading of MK on fibrinogen and enhanced formation of podosomes. Studies in humans have contributed significantly to our understanding of SRC signaling in platelets and MK.

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Rapid kinetics of second messenger production in bitter taste

AJP Cell Physiology ◽

10.1152/ajpcell.1996.270.3.c926 ◽

1996 ◽

Vol 270 (3) ◽

pp. C926-C931 ◽

Cited By ~ 56

Author(s):

A. I. Spielman ◽

H. Nagai ◽

G. Sunavala ◽

M. Dasso ◽

H. Breer ◽

...

Keyword(s):

Bitter Taste ◽

Second Messengers ◽

Second Messenger ◽

Mouse Strains ◽

Protective Mechanism ◽

Transient Nature ◽

Sucrose Octaacetate ◽

Rapid Kinetics ◽

First Time

The tasting of bitter compounds may have evolved as a protective mechanism against ingestion of potentially harmful substances. We have identified second messengers involved in bitter taste and show here for the first time that they are rapid and transient. Using a quench-flow system, we have studied bitter taste signal transduction in a pair of mouse strains that differ in their ability to taste the bitter stimulus sucrose octaacetate (SOA); however, both strains taste the bitter agent denatonium. In both strains of mice, denatonium (10 mM) induced a transient and rapid increase in levels of the second messenger inositol 1,4,5-trisphosphate (IP3) with a maximal production near 75-100 ms after stimulation. In contrast, SOA (100 microM) brought about a similar increase in IP3 only in SOA-taster mice. The response to SOA was potentiated in the presence of GTP (1 microM). The GTP-enhanced SOA-response supports a G protein-mediated response for this bitter compound. The rapid kinetics, transient nature, and specificity of the bitter taste stimulus-induced IP3 formation are consistent with the role of IP3 as a second messenger in the chemoelectrical transduction of bitter taste.

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