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The role of TRPC6 channels in neutrophil recruitment

TRPC6 通道在中性粒细胞募集中的作用

基本信息

批准号：
313658831
负责人：
Professor Dr. Albrecht Schwab
金额：
--
依托单位：
Institut für Physiologie II (Vegetative Physiologie)
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/313658831?language=en
关键词：
role TRPC6 channels neutrophil recruitment

项目摘要

The recruitment of neutrophil granulocytes from the blood follows a well defined sequence of events including rolling, adhesion and transmigration which is then followed by chemotaxis towards a lesion. Firm adhesion to endothelial cells is integrin-dependent and occurs as a result of activation of G-protein coupled receptors (GPCRs) for chemoattractants (e.g. CXCR2). CXCR2 contains like most other GPCRs an allosteric binding site for Na+ ions. Na+ binding inhibits constitutive GPCR activity which may be as high as 50 % of agonist-stimulated activity. Thus, Na+ binding within GPCRs appears to be a way to ensure the full dynamic range of receptor activation by agonists. CXCR2 ligands, classified as "intermediary chemoattractants", drive chemotaxis of neutrophils towards the vicinity of a lesion. "End target" chemoattractants, released within the lesion and prototypically represented by fMLP, then take over. Thus, chemoattractants act in a spatially distinct order during neutrophil recruitment. Neutrophil recruitment is Ca2+ dependent. We have shown that TRPC6 channels are functionally coupled to CXCR2-dependent steps. However, the contribution of other molecularly defined Ca2+ influx channels to individual steps of the recruitment cascade and the underlying mechanisms are not well characterized. Here we want to test the hypothesis whether (i) TRPC6 and TRPM2 channels are functionally coupled to intermediary and end target receptors, respectively, and thereby act at spatially distinct steps of the recruitment cascade. (ii) TRPC6-dependent mechanisms of firm adhesion will be studied in detail with atomic force microscopic techniques. Finally, we want to investigate, whether (iii) TRPC6 channels which are also permeable to Na+ ions, are linked to CXCR2 receptors by modifying allosteric binding of Na+ ions to the receptor protein via their impact on the intracellular Na+ concentration and/or the cell membrane potential.

中性粒细胞从血液中重新聚集遵循一系列明确的事件，包括滚动、粘连和移行，随后是对病变的趋化。与内皮细胞的牢固黏附是整合素依赖的，是G蛋白偶联受体(GPCRs)对趋化物质(如CXCR2)激活的结果。与大多数其他GPCRs一样，CXCR2含有一个与Na+离子的变构结合部位。Na+结合抑制结构性GPCR活性，其活性可能高达激动剂刺激活性的50%。因此，GPCRs内的Na+结合似乎是确保激动剂激活受体的整个动态范围的一种方式。CXCR2配体被归类为“中间趋化物质”，推动中性粒细胞向病变附近的趋化作用。“末端靶”化学诱导剂，在病变内释放，典型地由fMLP代表，然后接管。因此，在中性粒细胞募集过程中，化学吸引剂的作用顺序是不同的。中性粒细胞的募集依赖于钙离子。我们已经证明TRPC6通道在功能上与CXCR2依赖的步骤相连。然而，其他分子定义的钙离子内流通道对募集级联反应的各个步骤的贡献和潜在的机制还没有得到很好的描述。在这里，我们想检验这样的假设：(I)TRPC6和TRPM2通道是否在功能上分别与中间和终端靶标受体偶联，从而在招募级联的空间不同步骤中发挥作用。(Ii)将用原子力显微镜技术详细研究TRPC6依赖的公司粘合机制。最后，我们想要研究，(Iii)同样对Na+离子具有通透性的TRPC6通道是否通过影响细胞内Na+浓度和/或细胞膜电位而改变Na+与受体蛋白的变构结合而与CXCR2受体相连。