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Mechanisms of Platelet Activation and Integrin αIIβ3.

Joo SJ - Korean Circ J (2012)

Bottom Line: G protein-mediated signaling pathways, which are initiated by G(q), G(12)/G(13) or G(i), include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase.Rap1b, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin αIIbβ3.Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Division, Department of Internal Medicine, Jeju National University Hospital, Jeju, Korea.

ABSTRACT
Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane A(2) activate platelet integrin αIIbβ3 through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by G(q), G(12)/G(13) or G(i), include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin αIIbβ3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate.

No MeSH data available.


Related in: MedlinePlus

ADP receptors in the platelet. ADP binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelets shape. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of Gi-coupled P2Y12 receptor inhibits protein kinase C, and activates phosphatidylinositol 3-kinase, resulting in the activation of GP IIb/IIIa receptors and firm platelet aggregation. P2Y12 receptors are inhibited by ticlopidine or clopidogrel. AC: adenylyl cyclase, ADP: adenosine diphosphate, cAMP: cyclic adenosine monophosphate, GP: glycoprotein, PI3K: phosphatidylinositol 3-kinase, PLC: phospholipase C, PKC: protein kinase C.
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Figure 1: ADP receptors in the platelet. ADP binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelets shape. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of Gi-coupled P2Y12 receptor inhibits protein kinase C, and activates phosphatidylinositol 3-kinase, resulting in the activation of GP IIb/IIIa receptors and firm platelet aggregation. P2Y12 receptors are inhibited by ticlopidine or clopidogrel. AC: adenylyl cyclase, ADP: adenosine diphosphate, cAMP: cyclic adenosine monophosphate, GP: glycoprotein, PI3K: phosphatidylinositol 3-kinase, PLC: phospholipase C, PKC: protein kinase C.

Mentions: Adenosine diphosphate binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelet shape, but without platelet activation. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C (PLC) and induces a transient increase in intracellular calcium concentration resulting in platelet shape change and in weak, transient platelet aggregation. Stable and firm platelet aggregation requires ADP binding to P2Y12 receptor and activation of GPIIb/IIIa receptors in the platelets membrane.7) Activation of Gi-coupled P2Y12 receptor liberates the Gi protein subunits, αGi and βγ. The subunit αGi decreases the platelet cyclic adenosine monophosphate (cAMP) level through the inhibition of adenylyl cyclase. This decrease in cAMP production leads, in turn, to a reduction in the activation of protein kinase C (PKC), and, after complex signal transduction processes, activation of GP IIb/IIIa receptors (Fig. 1). The subunit βγ activates the phosphatidylinositol 3-kinase (PI-3K), which regulates protein kinase Akt and contributes to the activation of GP IIb/IIIa receptors.


Mechanisms of Platelet Activation and Integrin αIIβ3.

Joo SJ - Korean Circ J (2012)

ADP receptors in the platelet. ADP binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelets shape. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of Gi-coupled P2Y12 receptor inhibits protein kinase C, and activates phosphatidylinositol 3-kinase, resulting in the activation of GP IIb/IIIa receptors and firm platelet aggregation. P2Y12 receptors are inhibited by ticlopidine or clopidogrel. AC: adenylyl cyclase, ADP: adenosine diphosphate, cAMP: cyclic adenosine monophosphate, GP: glycoprotein, PI3K: phosphatidylinositol 3-kinase, PLC: phospholipase C, PKC: protein kinase C.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369959&req=5

Figure 1: ADP receptors in the platelet. ADP binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelets shape. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C resulting in weak, transient platelet aggregation. Activation of Gi-coupled P2Y12 receptor inhibits protein kinase C, and activates phosphatidylinositol 3-kinase, resulting in the activation of GP IIb/IIIa receptors and firm platelet aggregation. P2Y12 receptors are inhibited by ticlopidine or clopidogrel. AC: adenylyl cyclase, ADP: adenosine diphosphate, cAMP: cyclic adenosine monophosphate, GP: glycoprotein, PI3K: phosphatidylinositol 3-kinase, PLC: phospholipase C, PKC: protein kinase C.
Mentions: Adenosine diphosphate binding to P2X1 receptor results in rapid extracellular calcium influx, leading to alteration of platelet shape, but without platelet activation. ADP-stimulation of Gq-coupled P2Y1 receptor activates phospholipase C (PLC) and induces a transient increase in intracellular calcium concentration resulting in platelet shape change and in weak, transient platelet aggregation. Stable and firm platelet aggregation requires ADP binding to P2Y12 receptor and activation of GPIIb/IIIa receptors in the platelets membrane.7) Activation of Gi-coupled P2Y12 receptor liberates the Gi protein subunits, αGi and βγ. The subunit αGi decreases the platelet cyclic adenosine monophosphate (cAMP) level through the inhibition of adenylyl cyclase. This decrease in cAMP production leads, in turn, to a reduction in the activation of protein kinase C (PKC), and, after complex signal transduction processes, activation of GP IIb/IIIa receptors (Fig. 1). The subunit βγ activates the phosphatidylinositol 3-kinase (PI-3K), which regulates protein kinase Akt and contributes to the activation of GP IIb/IIIa receptors.

Bottom Line: G protein-mediated signaling pathways, which are initiated by G(q), G(12)/G(13) or G(i), include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase.Rap1b, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin αIIbβ3.Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor.

View Article: PubMed Central - PubMed

Affiliation: Cardiology Division, Department of Internal Medicine, Jeju National University Hospital, Jeju, Korea.

ABSTRACT
Platelet aggregation is not only an essential part of hemostasis, but also initiates acute coronary syndrome or ischemic stroke. The precise understanding of the activation mechanism of platelet aggregation is fundamental for the development of more effective agents against platelet aggregation. Adenosine diphosphate, thrombin, and thromboxane A(2) activate platelet integrin αIIbβ3 through G protein-coupled receptors. G protein-mediated signaling pathways, which are initiated by G(q), G(12)/G(13) or G(i), include phospholipase C with calcium signaling, Rho signaling, protein kinase C and phosphatidylinositol 3-kinase. Rap1b, Ca(2+) and diacylglycerol-regulated guanine nucleotide exchange factor I, Rap1-GTP-interacting adaptor molecule, and Akt are important proteins involved in G protein-mediated activation of integrin αIIbβ3. Binding of talin-1 and kindlin-3 to cytoplasmic domains of β3-integrin triggers a conformational change in the extracellular domains that increases its affinity for ligands, such as fibrinogen or von Willebrand factor. Fibrinogens act as bridges between adjacent platelets to generate a platelet aggregate.

No MeSH data available.


Related in: MedlinePlus