Ligands “activate” integrin αIIbβ3 (platelet GPIIb-IIIa)

Du, Xiaoping; Plow, Edward F.; Frelinger, Andrew L.; O’Toole, Timothy E.; Loftus, Joseph C.; Ginsberg, Mark H.

doi:10.1016/0092-8674(91)90458-b

Cited by 497 publications

(335 citation statements)

References 53 publications

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“…Platelets were washed with CGS buffer (0.12 M sodium chloride, 0.0129 M trisodium citrate, and 0.03 M D-glucose, pH 6.5), resuspended in modified Tyrode's solution at 3 ϫ 10 8 /ml, and allowed to incubate at 22°C for 1-2 h as described previously (23). In experiments using platelet-rich plasma (PRP), 1 ⁄10 volume of 3.8% trisodium citrate was used as anticoagulant.…”

Section: Methodsmentioning

confidence: 99%

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

Zhang

Marjanovic

et al. 2004

Journal of Biological Chemistry

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Platelet secretion (exocytosis) is critical in amplifying platelet activation, in stabilizing thrombi, and in arteriosclerosis and vascular remodeling. The signaling mechanisms leading to secretion have not been well defined. We have shown previously that cGMP-dependent protein kinase (PKG) plays a stimulatory role in platelet activation via the glycoprotein Ib-IX pathway. Here we show that PKG also plays an important stimulatory role in mediating aggregation-dependent platelet secretion and secretion-dependent second wave platelet aggregation, particularly those induced via G q -coupled agonist receptors, the thromboxane A2 (TXA2) receptor, and protease-activated receptors (PARs). PKG I knock-out mouse platelets and PKG inhibitor-treated human platelets showed diminished aggregation-dependent secretion and also showed a diminished secondary wave of platelet aggregation induced by a TXA2 analog and thrombin receptor-activating peptides that were rescued by the granule content ADP. Low dose collageninduced platelet secretion and aggregation were also reduced by PKG inhibitors. Furthermore PKG I knockout and PKG inhibitors significantly attenuated activation of the G i pathway that is mediated by secreted ADP. These data unveil a novel PKG-dependent platelet secretion pathway and a mechanism by which PKG promotes platelet activation.

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Section: Methodsmentioning

confidence: 99%

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

Zhang

Marjanovic

et al. 2004

Journal of Biological Chemistry

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“…2e). Ligand-mimetic antagonists are known to induce the conformation of α IIb β3 with high affinity for fibrinogen 14 .…”

Section: Overall Structure Of An Open Integrin Headpiecementioning

confidence: 99%

“…This marked change in tertiary structure is supported by mutational studies 3,6,[9][10][11] and solution X-ray scattering 12 . Ligand-mimetic compounds induce the extended, open headpiece conformation of integrins in solution and on the cell surface 3,6,[10][11][12][13] , and LIBS epitope exposure 14 . In contrast, when a ligand-mimetic is soaked into preformed crystals containing the bent integrin conformation with the closed headpiece, binding induces only localized structural changes near the ligand binding site 8 .…”

mentioning

confidence: 99%

Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

Xiao

Takagi

Coller

et al. 2004

Nature

767

1,177

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Integrins are important adhesion receptors in all Metazoa that transmit conformational change bidirectionally across the membrane. Integrin α and β subunits form a head and two long legs in the ectodomain and span the membrane. Here, we define with crystal structures the atomic basis for allosteric regulation of the conformation and affinity for ligand of the integrin ectodomain, and how fibrinogen-mimetic therapeutics bind to platelet integrin α IIb b β3 . Allostery in the β 3 I domain alters three metal binding sites, associated loops and a α1-and α7-helices. Piston-like displacement of the a 7-helix causes a 62° reorientation between the β 3 I and hybrid domains. Transmission through the rigidly connected plexin/semaphorin/integrin (PSI) domain in the upper β 3 leg causes a 70Å separation between the knees of the α and β legs. Allostery in the head thus disrupts interaction between the legs in a previously described low-affinity bent integrin conformation, and leg extension positions the high-affinity head far above the cell surface.Integrins are adhesion receptors that transmit signals bidirectionally across the plasma membrane 1-4 . Rearrangements in integrin extracellular, transmembrane and cytoplasmic domains underlie diverse biological processes, including cell migration, morpho-genesis, immune responses and vascular haemostasis. The platelet-specific integrin α IIb β 3 is important in both the arrest of bleeding at sites of vascular injury and pathological thrombosis leading to heart attacks and stroke. Loss of the vascular endothelium results in platelet deposition, and receptors for collagen, thrombin and other agonists then initiate

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“…The interaction of a IIb b 3 with surface-bound ligands is known to depend on the activation state of the integrin. In a study by Du et al (1991), small, RGDcontaining peptides changed the affinity of a IIb b 3 , leading to a better adhesion to surface-coated fibrinogen without inducing soluble fibrinogen binding. Our present findings are in line with these observations and suggest that an intracellular activation mechanism initiated by TPO induces similar changes to those seen with peptide additions.…”

Section: Figmentioning

confidence: 99%

Thrombopoietin increases platelet adhesion under flow and decreases rolling

Os¹,

Wu²,

Pouwels³

et al. 2003

Br J Haematol

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Summary. Thrombopoietin (TPO) is known to sensitize platelets to other agonists at 20 ng/ml, and above 100 ng/ml it is an independent activator of aggregation and secretion. In studies with a perfusion chamber, TPO, between 0AE01 ng/ml and 1 ng/ml, increased platelet adhesion to surface-coated fibrinogen, fibronectin and von Willebrand Factor (VWF) but not to a collagen-coated surface. Increased adhesion was observed at shear rates of 300/s and 800/s in perfusions with whole blood as well as in suspensions of platelets and red blood cells reconstituted in plasma. The by the cyclooxygenase inhibitor, indomethacin, and the thromboxane A 2 -receptor blocker, SQ30741, abolished the stimulation by TPO. The effect of TPO was mimicked by a very low concentration (10 nmol/l) of the thromboxane TxA 2 analogue, U46619. Real-time studies of platelet adhesion to a VWF-coated surface at a shear of 1000/s showed that about 20% of the platelets were in a rolling phase before they became firmly attached. TPO (1 ng/ml) pretreatment reduced this number to < 5%, an effect again abolished by indomethacin. Thus, TPO potentiates the direct and firm attachment of platelets to surface-coated ligands for a IIb b 3 , possibly by increasing the ligand affinity of the integrin.

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Ligands “activate” integrin αIIbβ3 (platelet GPIIb-IIIa)

Cited by 497 publications

References 53 publications

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

A Platelet Secretion Pathway Mediated by cGMP-dependent Protein Kinase

Structural basis for allostery in integrins and binding to fibrinogen-mimetic therapeutics

Thrombopoietin increases platelet adhesion under flow and decreases rolling

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