Integrin αIIbβ3

Błędzka, Kamila; Pesho, Michelle M.; Ma, Yanqing; Plow, Edward F.

doi:10.1016/b978-0-12-387837-3.00012-2

Cited by 11 publications

(12 citation statements)

References 286 publications

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“…The heterodimeric platelet receptor integrin αIIbβ3 mediates cell adhesion and plays a critical role in hemostasis and clot formation [1, 2]. Therefore, regulating the activity of αIIbβ3 is essential for platelet stimulation and prevention of their uncontrolled aggregation [3, 4].…”

Section: Introductionmentioning

confidence: 99%

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes

et al. 2019

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Integrins are transmembrane proteins involved in hemostasis, wound healing, immunity and cancer. In response to intracellular signals and ligand binding, integrins adopt different conformations: the bent (resting) form; the intermediate extended form; and the ligand-occupied active form. An integrin undergoing such conformational dynamics is the heterodimeric platelet receptor αIIbβ3. Although the dramatic rearrangement of the overall structure of αIIbβ3 during the activation process is potentially related to changes in the protein secondary structure, this has not been investigated so far in a membrane environment. Here we examine the Mn 2+ - and drug-induced activation of αIIbβ3 and the impact on the structure of this protein reconstituted into liposomes. By quartz crystal microbalance with dissipation monitoring and activation assays we show that Mn 2+ induces binding of the conformation-specific antibody PAC-1, which only recognizes the extended, active integrin. Circular dichroism spectroscopy reveals, however, that Mn 2+ -treatment does not induce major secondary structural changes of αIIbβ3. Similarly, we found that treatment with clinically relevant drugs (e.g. quinine) led to the activation of αIIbβ3 without significant changes in protein secondary structure. Molecular dynamics simulation studies revealed minor local changes in the beta-sheet probability of several extracellular domains of the integrin. Our experimental setup represents a new approach to study transmembrane proteins, especially integrins, in a membrane environment and opens a new way for testing drug binding to integrins under clinically relevant conditions.

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Section: Introductionmentioning

confidence: 99%

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes

et al. 2019

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“…To shed light on this issue, we compared MICT and HIIT concerning their effects on platelet function, as hyper-reactive platelets contribute both to atherogenesis5 and atherothrombosis 6. We assessed platelet function based on expression of P-selectin (CD62P, primary outcome) and CD40L (CD154), which are involved in atherogenesis,7 8 as well as GPIIb/IIIa activation, representing the molecular basis for thrombus formation 9…”

Section: Introductionmentioning

confidence: 99%

Effects of high-intensity interval training on platelet function in cardiac rehabilitation: a randomised controlled trial

Heber

Fischer

Sallaberger-Lehner³

et al. 2019

Heart

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ObjectiveTo compare effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on platelet function in patients undergoing cardiac rehabilitation, as hyper-reactive platelets are involved in atherogenesis and atherothrombosis.MethodsIn this single-centre parallel group randomised controlled trial, male patients after an acute coronary syndrome under dual antiplatelet therapy performed MICT or HIIT+MICT for 12 weeks. Main outcome was platelet reactivity measured by the half-maximal concentration (EC50) of platelet agonist thrombin receptor-activating peptide-6 (TRAP-6) in terms of P-selectin expression. EC50 was determined at baseline, after 6 and 12 weeks, each time at physical rest and on exertion.Results82 patients were randomised to MICT or HIIT+MICT. Mean (95% CI) baseline EC50values at physical rest were 6.7 µM (6.3 µM to 7.0 µM) TRAP-6. After 6/12 weeks, 36/33 MICT and 34/28 HIIT+MICT patients were examined. HIIT+MICT patients had 0.9 µM (0.4 µM to 1.4 µM)/0.5 µM (−0.1 µM to 1.0 µM) higher EC50values than MICT ones, and the propensity of their platelets to form aggregates with monocytes was significantly lower after 12 weeks. Short-term strenuous physical exertion was generally associated with platelet activation and an EC50reduction of 0.7 µM (0.6 µM to 0.8 µM). HIIT+MICT patients tended to be fitter after 12 weeks. No serious harms were observed.ConclusionsIncluding HIIT in cardiac rehabilitation seems to confer additional benefits compared with MICT alone, which should be confirmed in clinical trials with hard endpoints. Exertion-induced platelet activation and hyper-reactivity occur despite dual antiplatelet therapy.Trial registration numberNCT02930330; Results.

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“…Agonist-induced platelet activation triggers intracellular signaling events that converge at the cytoplasmic tails of αIIbβ3 and are then transmitted across the platelet membrane via inside-out signaling ultimately resulting in the transformation of the extracellular domain of αIIbβ3 into a high-affinity receptor for fibrinogen and VWF. 176,197,198 By binding divalent fibrinogen or multivalent VWF, 176,198 activated αIIbβ3 enables platelet-platelet interactions and consequently the formation of platelet aggregates. Moreover, by binding vitronectin, fibronectin, or thrombospondin-1, 199-201 activated αIIbβ3 may also mediate platelet adhesion to subendothelial structures and regulate platelet aggregation.…”

Section: Functionmentioning

confidence: 99%

“…Moreover, by binding vitronectin, fibronectin, or thrombospondin-1, 199-201 activated αIIbβ3 may also mediate platelet adhesion to subendothelial structures and regulate platelet aggregation. 197 The role of activated αIIbβ3 in platelet aggregation makes it a prime target for antithrombotic therapy (►Fig. 2).…”

Section: Functionmentioning

confidence: 99%

Platelet Physiology

Frelinger

Michelson

Gremmel

2016

Semin Thromb Hemost

256

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Platelets are the smallest blood cells, numbering 150 to 350???109/L in healthy individuals. The ability of activated platelets to adhere to an injured vessel wall and form aggregates was first described in the 19th century. Besides their long-established roles in thrombosis and hemostasis, platelets are increasingly recognized as pivotal players in numerous other pathophysiological processes including inflammation and atherogenesis, antimicrobial host defense, and tumor growth and metastasis. Consequently, profound knowledge of platelet structure and function is becoming more important in research and in many fields of modern medicine. This review provides an overview of platelet physiology focusing particularly on the structure, granules, surface glycoproteins, and activation pathways of platelets.

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Integrin αIIbβ3

Cited by 11 publications

References 286 publications

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes

Drug-induced activation of integrin alpha IIb beta 3 leads to minor localized structural changes

Effects of high-intensity interval training on platelet function in cardiac rehabilitation: a randomised controlled trial

Platelet Physiology

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