Is the mysterious platelet receptor GPV an unsuspected major target for platelet autoantibodies?

SummaryThe glycoprotein (GP) IIb/IIIa, a Ca2+-dependent heterodimer, is the major integrin on the platelet plasma membrane. On resting platelets GPIIb/IIIa is maintained in an inactive conformation and serves as a low affinity adhesion receptor for surface-coated fibrinogen, whereas upon platelet activation signals within the cytoplasma alter the receptor function of GPIIb/IIIa (inside-out signalling), which undergoes a measurable conformational change within its exoplasmic domains, and becomes a competent receptor for soluble fibrinogen and some other RGD sequence-containing plasma adhesive proteins. Upon ligand binding, further structural alterations trigger the association of receptor-occupied GPIIb/IIIa complexes with themselves within the plane of the membrane. The simultaneous binding of dimeric fibrinogen molecules to GPIIb/IIIa clusters on adjacent platelets leads to platelet aggregation, which promotes attachment of fibrinogen-GPIIb/IIIa clusters to the cytoskeleton (outside-in signalling). This, in turn, provides the necessary physical link for clot retraction to occur, and generates a cascade of intracellular biochemical reactions which result in the formation of a multiprotein signalling complex at the cytoplasmic domains of GPIIb/IIIa. Glycoprotein IMIIa, also called αIIbβ3 in the integrin nomenclature, plays thus a primary role in both platelet adhesion and thrombus formation at the site of vascular injury. In addition, the human glycoprotein Ilb/IIIa complex is the most thoroughly studied integrin receptor, its molecular biology and major features of its primary structure having been elucidated mainly during the last six years. Furthermore, localization of functionally relevant monoclonal antibody epitopes, determination of the cross-linking sites of inhibitory peptide ligands, proteolytic dissection of the isolated integrin, and analysis of natural and artificial GPIIb/IIIa mutants have recently provided a wealth of information regarding structure-function relationships of human GPIIb/IIIa. The aim of this review is to summarize these many structural and functional data in the perspective of an emerging model. Although most of the interpretations based on structural elements of this initial biochemical model require independent confirmation, they may help us to understand the structure-function relationship of this major platelet receptor, and of other members of the integrin superfamily, as well as to perform further investigations in order to test current hypotheses.

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Modulation of Platelet Activation by Native DNA – Initial Description of Platelet Receptor Type, Number and Discrimination for Native DNA

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650184 ◽

1981 ◽

Vol 45 (03) ◽

pp. 263-266 ◽

Cited By ~ 5

Author(s):

B A Fiedel ◽

M E Frenzke

Keyword(s):

Platelet Aggregation ◽

Human Platelets ◽

Scatchard Analysis ◽

Type Number ◽

Single Class ◽

Receptor Ligand ◽

Platelet Receptor ◽

Platelet Binding ◽

Ligand Interactions ◽

Initial Description

SummaryNative DNA (dsDNA) induces the aggregation of isolated human platelets. Using isotopically labeled dsDNA (125I-dsDNA) and Scatchard analysis, a single class of platelet receptor was detected with a KD = 190 pM and numbering ~275/platelet. This receptor was discriminatory in that heat denatured dsDNA, poly A, poly C, poly C · I and poly C · poly I failed to substantially inhibit either the platelet binding of, or platelet aggregation induced by, dsDNA; by themselves, these polynucleotides were ineffective as platelet agonists. However, poly G, poly I and poly G · I effectively and competitively inhibited platelet binding of the radioligand, independently activated the platelet and when used at a sub-activating concentration decreased the extent of dsDNA stimulated platelet aggregation. These data depict a receptor on human platelets for dsDNA and perhaps certain additional polynucleotides and relate receptor-ligand interactions to a physiologic platelet function.

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G4120, an Arg-Gly-Asp Containing Pentapeptide, Enhances Arterial Eversion Graft Recanalization with Recombinant Tissue-Type Plasminogen Activator in Dogs

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648523 ◽

1992 ◽

Vol 67 (06) ◽

pp. 686-691 ◽

Cited By ~ 12

Author(s):

Hua Rong Lu ◽

Herman K Gold ◽

Zaomin Wu ◽

Tsunehiro Yasuda ◽

Patrick Pauwels ◽

...

Keyword(s):

Plasminogen Activator ◽

Arterial Occlusion ◽

Tissue Type ◽

Clot Lysis ◽

Arterial Graft ◽

Tissue Type Plasminogen Activator ◽

Group I ◽

Type Plasminogen Activator ◽

Platelet Receptor ◽

Observation Period

SummaryThe effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial thrombus model consisted of a 3 cm everted (inside-out) carotid arterial segment inserted into a transsected femoral artery which occludes within 30 min with platelet-rich material and which is resistant to recanalization with 0.5 mg/kg rt-PA. The venous thrombus was a 125I-fibrin labeled whole blood clot produced in the contralateral femoral vein.In 5 dogs given an intravenous bolus of 0.05 mg/kg G4120 followed by a continuous infusion of 0.05 mg/kg per hour for 3 h (group I), arterial occlusion persisted throughout a 4 h observation period and was still present at 24 h in all dogs; the extent of venous clot lysis after 120 min was 27 ± 7%. In 5 dogs given the same infusion of G4120 in combination with 0.5 mg/kg rt-PA over 60 min, recanalization of the arterial graft occurred in all dogs, within 13 ± 2 min and persisted throughout the observation period of 4 h (p = 0.01 versus G4120 or rt-PA alone); at 24 h, however, all grafts were occluded. Venous clot lysis in this group was 75 ± 8% (p = 0.002 versus G4120 alone andp NS versus rt-PA alone). Pathologic analysis revealed platelet-rich or mixed thrombus with platelet-rich and erythrocyte-rich zones. The last 6 dogs were given a reduced dose of G4120 consisting either of a 0.05 mg/kg bolus followed by an infusion of 0.05 mg/kg over 1 h in 3 dogs (group III) or of a single 0.05 mg/kg bolus in 3 dogs (group IV), both given in combination with 0.5 mg/kg rt-PA infused over 60 min. These protocols produced recanalization within 15 ± 2 and 34 ± 8 min, respectively, which was maintained throughout the 4 h observation period. Venous lysis in these groups was 63 ± 4 and 97 ± 1% respectively. Bleeding times prolonged from 1 to 2 min to >30 min with G4120, but returned towards baseline within 2 h after the end of the infusion. Platelet aggregation with ADP was completely inhibited with G4120 but partially recovered within 1 h after the end of the infusion. No fibrinogen breakdown was observed in association with the rt-PA infusion.Thus, G4120, a synthetic GPIIb/IIIa receptor antagonist, enhances and accelerates lysis of platelet-rich arterial thrombosis with rt-PA and prevents reocclusion during and within 3 h after the infusion. It may be useful for the conjunctive use with thrombolytic agents in patients with arterial thromboembolic disease.

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Autophagy: A Major Target of Cadmium Nephrotoxicity

Current Chemical Biology ◽

10.2174/2212796811307020009 ◽

2013 ◽

Vol 7 (2) ◽

pp. 177-187

Author(s):

Abderrahman Chargui ◽

Amine Belaïd ◽

Nadir Djerbi ◽

Michèle El May ◽

Baharia Mograbi

Keyword(s):

Major Target

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Amino Acid Sequences in Fibrinogen Mediating Its Interaction with Its Platelet Receptor, GPIIbIIIa

Journal of Biological Chemistry ◽

10.1016/s0021-9258(18)60523-x ◽

1989 ◽

Vol 264 (16) ◽

pp. 9258-9265 ◽

Cited By ~ 3

Author(s):

A Andrieux ◽

G Hudry-Clergeon ◽

J J Ryckewaert ◽

A Chapel ◽

M H Ginsberg ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Sequences ◽

Platelet Receptor

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Fascial or Muscle Stretching? A Narrative Review

Applied Sciences ◽

10.3390/app11010307 ◽

2020 ◽

Vol 11 (1) ◽

pp. 307

Author(s):

Carla Stecco ◽

Carmelo Pirri ◽

Caterina Fede ◽

Can A. Yucesoy ◽

Raffaele De Caro ◽

...

Keyword(s):

Muscular Contraction ◽

Deep Fascia ◽

Static Stretching ◽

Force Transmission ◽

Myofascial Force Transmission ◽

Biomechanical Behavior ◽

Passive Stretching ◽

Muscle Stretching ◽

Major Target ◽

Stretching Exercises

Stretching exercises are integral part of the rehabilitation and sport. Despite this, the mechanism behind its proposed effect remains ambiguous. It is assumed that flexibility increases, e.g., action on muscle and tendon, respectively, but this is not always present in the stretching protocol of the exercises used. Recently, the fasciae have increased popularity and seems that they can have a role to define the flexibility and the perception of the limitation of the maximal range of motion (ROM). Deep fascia is also considered a key element to transmit load in parallel bypassing the joints, transmitting around 30% of the force generated during a muscular contraction. So, it seems impossible dividing the action of the muscles from the fasciae, but they have to be considered as a “myofascial unit”. The purpose of this manuscript is to evaluate the mechanical behavior of muscles, tendons, and fasciae to better understand how they can interact during passive stretching. Stress-strain values of muscle, tendon and fascia demonstrate that during passive stretching, the fascia is the first tissue that limit the elongation, suggesting that fascial tissue is probably the major target of static stretching. A better understanding of myofascial force transmission, and the study of the biomechanical behavior of fasciae, with also the thixotropic effect, can help to design a correct plan of stretching.

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