Structure and function of the platelet integrin  IIb 3

Bennett, Joel S.

doi:10.1172/jci26989

Cited by 324 publications

(260 citation statements)

References 99 publications

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“…In the next set of experiments, we investigated whether the increased aggregation response observed in the e‐cigarette–exposed mice is accompanied by a commensurate elevation in integrin GPIIb‐IIIa (α IIb β 3 ) activation; which is required for platelet aggregation 56. We observed that the activation of the α IIb β 3 integrin is enhanced in e‐cigarette–exposed platelets, compared with the clean air exposure, in response to ADP and U46619 (Figure 5A and 5B; the percentage of α IIb β 3 ‐positive cells induced by ADP was 76.33±2.35 [e‐cigarettes] versus 49±3.46 [clean air]; P =0.0028; whereas that induced by U46619 was 85.67±2.33 [e‐cigarettes] versus 59.33±3.18 [clean air]; P =0.0023).…”

Section: Resultsmentioning

confidence: 99%

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Qasim

Karim

Silva‐Espinoza

et al. 2018

JAHA

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BackgroundCardiovascular disease is the main cause of death in the United States, with smoking being the primary preventable cause of premature death, and thrombosis being the main mechanism of cardiovascular mortality in smokers. Due to the perception that electronic/e‐cigarettes are “safer/less harmful” than conventional cigarettes, their usage—among a variety of ages—has increased tremendously during the past decade. Notably, there are limited studies regarding the negative effects of e‐cigarettes on the cardiovascular system, which is also the subject of significant debate.Methods and ResultsWe employed a passive e‐VapeTM vapor inhalation system and developed an in vivo whole‐body e‐cigarette mouse exposure protocol that mimics real‐life human exposure scenarios/conditions and investigated the effects of e‐cigarettes and clean air on platelet function and thrombogenesis. Our results show that platelets from e‐cigarette–exposed mice are hyperactive, with enhanced aggregation, dense and α granule secretion, activation of the αIIbβ3 integrin, phosphatidylserine expression, and Akt and ERK activation, when compared with clean air–exposed platelets. E‐cigarette–exposed platelets were also found to be resistant to inhibition by prostacyclin, relative to clean air. Furthermore, the e‐cigarette–exposed mice exhibited a shortened thrombosis occlusion and bleeding times.ConclusionsTaken together, our data demonstrate for the first time that e‐cigarettes alter physiological hemostasis and increase the risk of thrombogenic events. This is attributable, at least in part, to the hyperactive state of platelets. Thus, the negative health consequences of e‐cigarette exposure should not be underestimated and warrant further investigation.

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Section: Resultsmentioning

confidence: 99%

Short‐Term E‐Cigarette Exposure Increases the Risk of Thrombogenesis and Enhances Platelet Function in Mice

Qasim

Karim

Silva‐Espinoza

et al. 2018

JAHA

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“…T he integrin αIIbβ3 resides on the platelet surface in equilibrium between resting and active conformations (1)(2)(3)(4)(5). On circulating platelets, αIIbβ3 is constrained in its inactive conformation to prevent spontaneous platelet aggregation.…”

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confidence: 99%

Affinity of talin-1 for the β3-integrin cytosolic domain is modulated by its phospholipid bilayer environment

Moore

Nygren

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Binding of the talin-1 FERM (4.1/ezrin/radixin/moesin) domain to the β3 cytosolic tail causes activation of the integrin αIIbβ3. The FERM domain also binds to acidic phospholipids. Although much is known about the interaction of talin-1 with integrins and lipids, the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Here, we examined the thermodynamic interplay between FERM domain binding to phospholipid bilayers and to its binding sites in the β3 tail. We found that although both the F0F1 and F2F3 subdomains of the talin-1 FERM domain bind acidic bilayers, the full-length FERM domain binds with an affinity similar to F2F3, indicating that F0F1 contributes little to the overall interaction. When free in solution, the β3 tail has weak affinity for the FERM domain. However, appending the tail to acidic phospholipids increased its affinity for the FERM domain by three orders of magnitude. Nonetheless, the affinity of the FERM for the appended tail was similar to its affinity for binding to bilayers alone. Thus, talin-1 binding to the β3 tail is a ternary interaction dominated by a favorable surface interaction with phospholipid bilayers and set by lipid composition. Nonetheless, interactions between the FERM domain, the β3 tail, and lipid bilayers are not optimized for a high-affinity synergistic interaction, even at the membrane surface. Instead, the interactions appear to be tuned in such a way that the equilibrium between inactive and active integrin conformations can be readily regulated.cytoskeleton | plasma membrane | platelet aggregation T he integrin αIIbβ3 resides on the platelet surface in equilibrium between resting and active conformations (1-5). On circulating platelets, αIIbβ3 is constrained in its inactive conformation to prevent spontaneous platelet aggregation. Similarly, the cytoskeletal protein talin-1, whose binding to the β3 cytosolic tail (CT) stabilizes the active conformation of αIIbβ3 (6-8), is sequestered away from the β3 CT (9). Besides interacting with integrins, talin-1 interacts with negatively charged phospholipids (10-12) and phosphoinositides (13)(14)(15)(16). Stimuli generated at sites of vascular damage recruit talin-1 to the platelet plasma membrane, thereby promoting αIIbβ3 activation (17-19). Much is known about the interaction of talin-1 with integrins and lipids, but the relative contribution of each interaction to integrin regulation and possible synergy between them remain to be clarified. Elucidating these interactions is important for understanding events leading to and controlling the formation of integrin complexes and for potential pharmacologic modulation of integrin signaling.Talin-1 is a 250-kD protein containing a 45-kD N-terminal head domain attached via a flexible linker to a 200-kD C-terminal rod domain (7). Because the head domain is packed against the rod domain in its inactive state (20), talin-1 recruitment to the membrane and to integrin β CTs requires disruption of this interaction (1...

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“…Ligation of platelet GPIb to endothelial cell von Willebrand factor during platelet rolling lead to activation of platelet integrin (Kasirer-Friede et al, 2002). Integrins are ubiquitous transmembrane / heterodimers that mediate cell-matrix and cell-cell interactions (Bennet, 2005). Platelets express 3 members of the 1 subfamily ( II 1, v 1, and vI 1) and 2 members of the 3 subfamily ( v 3 and IIb 3) (Bennet, 2005).…”

Section: Tight Adhesion Of Platelet To Endothelial Cell Surfacementioning

confidence: 99%

“…Integrins are ubiquitous transmembrane / heterodimers that mediate cell-matrix and cell-cell interactions (Bennet, 2005). Platelets express 3 members of the 1 subfamily ( II 1, v 1, and vI 1) and 2 members of the 3 subfamily ( v 3 and IIb 3) (Bennet, 2005). An IIb 3 is the most important integrin on platelets (Gawaz et al, 1991).…”

Section: Tight Adhesion Of Platelet To Endothelial Cell Surfacementioning

confidence: 99%