scholarly journals Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 2

2018 ◽  
Vol 38 (04) ◽  
pp. 211-222
Author(s):  
Rüdiger Scharf
Keyword(s):  
Thrombus Formation ◽  
Fluid Phase ◽  
G Protein Coupled Receptors ◽  
Microbial Pathogens ◽  
Extracellular Traps ◽  
Signaling Mechanisms ◽  
Arterial Thrombus ◽  
Platelet Signaling ◽  
Genetically Determined ◽  
G Protein Coupled

AbstractPlatelet signal transduction is the focus of this review. While ‘classic’ platelet signaling through G protein–coupled receptors in response to fluid-phase agonists has been extensively studied, signaling mechanisms linking platelet adhesion receptors such as GPIb-IX-V, GPVI and α2β1 to the activation of αIIbβ3 are less well established. Moreover, ‘non-haemostatic’ pathways can also activate platelets in various settings, including platelet–immune or platelet–tumour cell interactions, platelet responses to neutrophil extracellular traps, or stimulation by microbial pathogens. Genetically determined integrin variants can modulate platelet function and increase thrombogenicity. A typical example is the Pro33 (HPA-1b) variant of αIIbβ3. Recent advances in the genotype–phenotype relation of this prothrombotic variant and its impact on outside-in signaling will be reviewed.

Platelet Signaling in Primary Haemostasis and Arterial Thrombus Formation: Part 1

2018 ◽  
Vol 38 (04) ◽  
pp. 203-210 ◽  
Author(s):  
Rüdiger Scharf
Keyword(s):  
Platelet Activation ◽  
Thrombus Formation ◽  
Vascular Lesions ◽  
Arterial Thrombus ◽  
Platelet Signaling ◽  
Transduction Mechanisms ◽  
Granule Secretion ◽  
Von Willebrand ◽  
The Impact

AbstractPlatelets react immediately in response to traumatic vascular injury by adhesion, activation, aggregation and subsequent haemostatic plug formation. While this reaction pattern is essential for haemostasis, platelet responses can also cause occlusive thrombi in diseased arteries, leading to myocardial infarction or stroke. Initially, flowing platelets are captured from the circulation to vascular lesions. This step is mediated by glycoprotein (GP) Ib-IX-V interacting with immobilized von Willebrand factor (VWF) on exposed subendothelial components. Tethered platelets can now bind to collagen through GPVI and integrin α2β1. Outside-in signals from the adhesion receptors act synergistically with inside-out signals from soluble stimuli and induce platelet activation. These mediators operate through G protein–coupled receptors and reinforce adhesion and activation. Typical manifestations of activated platelets include calcium mobilization, procoagulant activity, cytoskeletal reorganization, granule secretion and aggregation. This requires activation of integrin αIIbβ3 with shifting into a high-affinity state and is indispensable to bind soluble fibrinogen, VWF and fibronectin. The multiple interactions and the impact of thrombin result in firm adhesion and recruitment of circulating platelets into growing aggregates. A fibrin meshwork supports stabilization of haemostatic thrombi and prevents detachment by the flowing blood. This two-part review provides an overview of platelet activation and signal transduction mechanisms with a focus on αIIbβ3-mediated outside-in signaling in integrin variants. In the first part, a three-stage model of platelet recruitment and activation in vivo is presented. Along with that, platelet responses upon exposure to thrombogenic surfaces followed by platelet-to-platelet interactions and formation of haemostatic thrombi are discussed. Moreover, several determinants involved in pathological thrombosis will be reviewed.

scholarly journals The expanding functional roles and signaling mechanisms of adhesion G protein–coupled receptors

2019 ◽  
Vol 1456 (1) ◽  
pp. 5-25 ◽  
Author(s):  
Rory K. Morgan ◽  
Garret R. Anderson ◽  
Demet Araç ◽  
Gabriela Aust ◽  
Nariman Balenga ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Functional Roles ◽  
Signaling Mechanisms ◽  
G Protein Coupled ◽  
Mechanisms Of Adhesion

Continuous signaling via PI3K isoforms β and γ is required for platelet ADP receptor function in dynamic thrombus stabilization

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3045-3052 ◽  
Author(s):  
Judith M. E. M. Cosemans ◽  
Imke C. A. Munnix ◽  
Reinhard Wetzker ◽  
Regine Heller ◽  
Shaun P. Jackson ◽  
...  
Keyword(s):  
Thrombus Formation ◽  
G Protein Coupled Receptors ◽  
Platelet Aggregate ◽  
Platelet Aggregates ◽  
Adp Receptor ◽  
Phosphoinositide 3 Kinase ◽  
Novel Concept ◽  
Induced Aggregation ◽  
G Protein Coupled ◽  
Intrinsic Dynamic

Abstract Signaling from collagen and G protein–coupled receptors leads to platelet adhesion and subsequent thrombus formation. Paracrine agonists such as ADP, thromboxane, and Gas6 are required for platelet aggregate formation. We hypothesized that thrombi are intrinsically unstable structures and that their stabilization requires persistent paracrine activity and continuous signaling, maintaining integrin αIIbβ3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated (1) in the absence of fibrinogen-containing plasma; (2) by blocking or inhibiting αIIbβ3; (3) by blocking P2Y12 receptors; (4) by suppression of phosphoinositide 3-kinase (PI3K) β. In murine blood, absence of PI3Kγ led to formation of unstable thrombi, leading to dissociation of multiplatelet aggregates. In addition, blocking PI3Kβ delayed initial thrombus formation and reduced individual platelet-platelet contact. Similarly without flow, agonist-induced aggregation was reversed by late suppression of P2Y12 or PI3K isoforms, resulting in single platelets that had inactivated αIIbβ3 and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y12 and both PI3Kβ and PI3Kγ isoforms is required for perpetuated αIIbβ3 activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of antiplatelet therapy.

scholarly journals New functions and signaling mechanisms for the class of adhesion G protein-coupled receptors

2014 ◽  
Vol 1333 (1) ◽  
pp. 43-64 ◽  
Author(s):  
Ines Liebscher ◽  
Brian Ackley ◽  
Demet Araç ◽  
Donna M. Ariestanti ◽  
Gabriela Aust ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Signaling Mechanisms ◽  
G Protein Coupled

A combination of pharmacophore modeling, molecular docking, and virtual screening for P2Y12 receptor antagonists from Chinese herbs

2015 ◽  
Vol 93 (3) ◽  
pp. 311-316 ◽  
Author(s):  
Yusu He ◽  
Ludi Jiang ◽  
Zhen Yang ◽  
Yanjiang Qiao ◽  
Yanling Zhang
Keyword(s):  
Drug Target ◽  
Thrombus Formation ◽  
Pharmacophore Modeling ◽  
G Protein Coupled Receptors ◽  
Chinese Herbs ◽  
Receptor Antagonists ◽  
Hydrogen Bond Acceptor ◽  
Reliable Source ◽  
G Protein Coupled ◽  
Pharmacophore Models

P2Y12, a member of the G-protein-coupled receptors, is associated with abnormal platelet aggregation, a condition that contributes to thrombus formation. As receptor antagonists are effective solutions for anti-thrombus, the P2Y12 receptor is a popular drug target. After the recent resolution of the P2Y12 receptor’s crystal structure, pharmacophore modeling and docking were combined to discover potential natural antagonists. Various approaches were used for the validation of the pharmacophore models and the optimization of docking algorithms. Hypo18, which was generated by 24 known antagonists, was determined to be the best hypothesis and is comprised of one ring aromatic, one hydrogen bond acceptor, one exclude volume, and three hydrophobic features. Hypo18 was thus utilized to screen TCMD (version 2009) to identify any potential active compounds, which then resulted in a hit list of 121 compounds with drug-likeness analysis. In addition, docking was used to refine the pharmacophore-based screening results as a cross-linking method. Then, the top 20 compounds with high docking scores were reserved. This paper provides a reliable source for discovering natural P2Y12 receptor antagonists from traditional Chinese herbs.

scholarly journals Lactate as an Astroglial Signal Augmenting Aerobic Glycolysis and Lipid Metabolism

2021 ◽  
Vol 12 ◽  
Author(s):  
Anemari Horvat ◽  
Robert Zorec ◽  
Nina Vardjan
Keyword(s):  
Lipid Metabolism ◽  
Brain Function ◽  
Lipid Droplets ◽  
Aerobic Glycolysis ◽  
Lactate Production ◽  
G Protein Coupled Receptors ◽  
Camp Production ◽  
Signaling Mechanisms ◽  
G Protein Coupled ◽  
The Brain

Astrocytes, heterogeneous neuroglial cells, contribute to metabolic homeostasis in the brain by providing energy substrates to neurons. In contrast to predominantly oxidative neurons, astrocytes are considered primarily as glycolytic cells. They take up glucose from the circulation and in the process of aerobic glycolysis (despite the normal oxygen levels) produce L-lactate, which is then released into the extracellular space via lactate transporters and possibly channels. Astroglial L-lactate can enter neurons, where it is used as a metabolic substrate, or exit the brain via the circulation. Recently, L-lactate has also been considered to be a signaling molecule in the brain, but the mechanisms of L-lactate signaling and how it contributes to the brain function remain to be fully elucidated. Here, we provide an overview of L-lactate signaling mechanisms in the brain and present novel insights into the mechanisms of L-lactate signaling via G-protein coupled receptors (GPCRs) with the focus on astrocytes. We discuss how increased extracellular L-lactate upregulates cAMP production in astrocytes, most likely viaL-lactate-sensitive Gs-protein coupled GPCRs. This activates aerobic glycolysis, enhancing L-lactate production and accumulation of lipid droplets, suggesting that L-lactate augments its own production in astrocytes (i.e., metabolic excitability) to provide more L-lactate for neurons and that astrocytes in conditions of increased extracellular L-lactate switch to lipid metabolism.

scholarly journals Current Concepts and Treatments of Schizophrenia

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2087 ◽  
Author(s):  
Piotr Stępnicki ◽  
Magda Kondej ◽  
Agnieszka A. Kaczor
Keyword(s):  
Social Withdrawal ◽  
G Protein Coupled Receptors ◽  
Positive Symptoms ◽  
Allosteric Modulators ◽  
Attention Disorders ◽  
Flat Affect ◽  
Receptor Oligomerization ◽  
Signaling Mechanisms ◽  
Thought Disorders ◽  
G Protein Coupled

Schizophrenia is a debilitating mental illness which involves three groups of symptoms, i.e., positive, negative and cognitive, and has major public health implications. According to various sources, it affects up to 1% of the population. The pathomechanism of schizophrenia is not fully understood and current antipsychotics are characterized by severe limitations. Firstly, these treatments are efficient for about half of patients only. Secondly, they ameliorate mainly positive symptoms (e.g., hallucinations and thought disorders which are the core of the disease) but negative (e.g., flat affect and social withdrawal) and cognitive (e.g., learning and attention disorders) symptoms remain untreated. Thirdly, they involve severe neurological and metabolic side effects and may lead to sexual dysfunction or agranulocytosis (clozapine). It is generally agreed that the interactions of antipsychotics with various neurotransmitter receptors are responsible for their effects to treat schizophrenia symptoms. In particular, several G protein-coupled receptors (GPCRs), mainly dopamine, serotonin and adrenaline receptors, are traditional molecular targets for antipsychotics. Comprehensive research on GPCRs resulted in the exploration of novel important signaling mechanisms of GPCRs which are crucial for drug discovery: intentionally non-selective multi-target compounds, allosteric modulators, functionally selective compounds and receptor oligomerization. In this review, we cover current hypotheses of schizophrenia, involving different neurotransmitter systems, discuss available treatments and present novel concepts in schizophrenia and its treatment, involving mainly novel mechanisms of GPCRs signaling.

Isoprostane-induced airway hyperresponsiveness is dependent on internal Ca2+ handling and Rho/ROCK signaling

2006 ◽  
Vol 291 (6) ◽  
pp. L1177-L1184 ◽  
Author(s):  
Caiqiong Liu ◽  
Tracy Tazzeo ◽  
Luke J. Janssen
Keyword(s):  
Airway Hyperresponsiveness ◽  
Rho Kinase ◽  
Cyclopiazonic Acid ◽  
Threshold Concentration ◽  
Effective Concentration ◽  
G Protein Coupled Receptors ◽  
Rock Inhibitor ◽  
Signaling Mechanisms ◽  
G Protein Coupled ◽  
Cholinergic Response

We previously reported the ability of isoprostanes to induce airway hyperresponsiveness (AHR). In this study, we examined the signaling mechanisms underlying that phenomenon with the standard muscle bath technique. Responses to a threshold concentration of carbachol (CCh, 3 × 10−9 M) were significantly augmented by pretreatment for 20 min with 8-isoprostaglandin E2 (15-E2t-IsoP, 10−6 M): this AHR was obliterated in tissues pretreated with the selective Rho kinase (ROCK) inhibitor Y-27632 added 20 min before isoprostane, but not by cyclopiazonic acid (CPA). Increasing the CCh concentration to 3 × 10−8 M (still considerably less than the half-maximally effective concentration of CCh) evoked larger contractions that were also augmented significantly by 15-E2t-IsoP: this AHR was completely abolished in tissues pretreated with CPA as well as those pretreated with Y-27632. We noted, however, that Y-27632 and CPA profoundly effect baseline tone and the cholinergic response per se, which confounds the interpretation of the data summarized above. We therefore modified the protocol by using combinations of CCh and blocker (CPA, Y-27632, or nifedipine) that were equieffective. In this way, we found that AHR could not be demonstrated under conditions in which Rho/ROCK signaling or Ca2+ release was abolished (by Y-27632 and CPA, respectively). Likewise, other autacoids that act through G protein-coupled receptors via Rho/ROCK and Ca2+ release (serotonin, histamine) mimicked this effect of isoprostane, whereas bradykinin did not. We conclude that isoprostane-induced AHR is mediated in part through an action on Rho/ROCK signaling. This novel finding may contribute to a better understanding of the mechanisms underlying AHR and asthma.

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