Mechanisms of Adhesion GPCR Action

粘附 GPCR 作用机制

基本信息

项目摘要

Summary/Abstract: GPR56/ADGRG1 is a deorphanized brain Adhesion G protein Coupled Receptor (AGPCR) with a physiological ligand, collagen. We present new evidence that GPR56 is present on the surface of human and mouse platelets. This is very intriguing considering that autonomous platelet activation that leads to clot formation is mediated by platelet interactions with collagen that becomes exposed at sites of vessel injury. We found that pharmacological activation of platelet GPR56 is sufficient to elicit the physiological platelet activation program required for wound healing (hemostasis) and blood clotting (thrombosis). Moreover, Gpr56 knockout mice have a severe bleeding disorder and dramatic defects in clot formation in mouse vessel wall injury models. We hypothesize that GPR56 is the platelet collagen receptor that mediates the initial G protein 12/13-dependent platelet shape changes while platelets roll/translocate along exposed collagen to their site of stable adhesion at the lagging edges of blood vessel wounds. We will investigate platelet GPR56-mediated G protein signaling, platelet shape changes, in vitro platelet activation, and the role of GPR56 in mouse models of hemostasis and thrombosis. We found compelling preliminary evidence that platelets from Gpr56 knockout mice are dramatically defective in adhering to an immobilized collagen surface when mouse blood is flowed over the surface at high shear force. We propose that GPR56 is not directly involved in stable platelet adhesion, but as platelets tumble across the collagen surface, GPR56 is stimulated to cause the shape changes that allow platelets to then stably adhere via distinct non-GPCR collagen receptors. Before discovering GPR56 on platelets we proposed a general model of AGPCR activation that required anchoring of the receptor N-termini, and shear force-mediated receptor dissociation that leads to exposure of the AGPCR tethered agonists to induce G protein signaling. The conditions experienced by platelet-borne GPR56 align remarkably well with this theoretical model. Our work also includes conducting biochemical studies using newly developed photo-crosslinking agonist probes to define the agonist binding sites of the related AGPCRs, GPR56 and GPR114.
摘要/摘要:GPR56/ADGRG1是一种去孤构化的脑黏附G蛋白偶联受体(AGPCR) 使用一种生理配基--胶原蛋白。我们提出了GPR56存在于人类表面的新证据 和小鼠的血小板。这是非常耐人寻味的,因为自主的血小板激活会导致血栓 形成是通过血小板与胶原的相互作用,在血管损伤部位暴露出来的。我们 研究发现,GPR56的药理激活足以诱导生理上的血小板激活 伤口愈合(止血)和血液凝固(血栓形成)所需的程序。此外,Gpr56基因敲除 在小鼠血管壁损伤模型中,小鼠存在严重的出血障碍和严重的血栓形成缺陷。 我们假设GPR56是介导初始G蛋白12/13依赖的血小板胶原受体 当血小板沿着暴露的胶原滚动/转移到其稳定粘连的位置时,血小板的形状会发生变化。 血管伤口的滞后边缘。我们将研究血小板GPR56介导的G蛋白信号转导, 小鼠止血模型中的血小板形态变化、体外血小板活化及GPR56的作用 血栓形成。我们发现了令人信服的初步证据,来自Gpr56基因敲除小鼠的血小板显著 当小鼠血液以较高的速度流过固定的胶原蛋白表面时,粘附性有缺陷 剪切力。我们认为,GPR56不直接参与稳定的血小板黏附,而是当血小板翻滚时 在整个胶原表面,GPR56被刺激导致形状变化,从而使血小板稳定地 通过不同的非GPCR型胶原蛋白受体黏附。在发现血小板上的GPR56之前,我们提出了一个 需要锚定受体N-末端和剪切力介导的AGPCR激活的一般模型 受体解离,导致AGPCR拴系激动剂暴露,诱导G蛋白信号转导。这个 血小板携带的GPR56所经历的情况与这一理论模型非常吻合。我们的工作 还包括使用新开发的光交联激动剂探针进行生化研究,以确定 相关AGPCRs的激动剂结合部位GPR56和GPR114。

项目成果

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Gregory Gordon Tall其他文献

Gregory Gordon Tall的其他文献

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{{ truncateString('Gregory Gordon Tall', 18)}}的其他基金

Investigation of Adhesion GPCR and Ric-8 protein control of heterotrimeric G proteins
异三聚体 G 蛋白粘附 GPCR 和 Ric-8 蛋白控制的研究
  • 批准号:
    10622696
  • 财政年份:
    2023
  • 资助金额:
    $ 36.66万
  • 项目类别:
Development of Chemical Probes to Investigate Adhesion GPCR Tethered Agonism
开发用于研究粘附 GPCR 系链激动作用的化学探针
  • 批准号:
    9917826
  • 财政年份:
    2018
  • 资助金额:
    $ 36.66万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    10374884
  • 财政年份:
    2016
  • 资助金额:
    $ 36.66万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9352861
  • 财政年份:
    2016
  • 资助金额:
    $ 36.66万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9981283
  • 财政年份:
    2016
  • 资助金额:
    $ 36.66万
  • 项目类别:
Mechanisms of Adhesion GPCR Action
粘附 GPCR 作用机制
  • 批准号:
    9155400
  • 财政年份:
    2016
  • 资助金额:
    $ 36.66万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    8534176
  • 财政年份:
    2009
  • 资助金额:
    $ 36.66万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    9336939
  • 财政年份:
    2009
  • 资助金额:
    $ 36.66万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    8136505
  • 财政年份:
    2009
  • 资助金额:
    $ 36.66万
  • 项目类别:
Regulation of heterotrimeric G proteins by non-receptor activators
非受体激活剂对异源三聚体 G 蛋白的调节
  • 批准号:
    8757091
  • 财政年份:
    2009
  • 资助金额:
    $ 36.66万
  • 项目类别:

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