The role of the nucleotide-gated cation channels P2X7 and TRPM2 for TCR signalling

核苷酸门控阳离子通道 P2X7 和 TRPM2 在 TCR 信号传导中的作用

• 批准号: 263128973
• 负责人: Professor Dr. Andreas H. Guse
• 金额: --
• 依托单位: Institut für Biochemie und Molekulare Zellbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/263128973?language=en
• 关键词: role; nucleotide; gated; cation; channels

P2X7 and TRPM2 are cation channels expressed by T lymphocytes that are gated by extra- and intracellular adenine nucleotides, respectively. Although increasing evidence points to a pivotal role of both channels in inflammation, their effects on T cells remain unclear. The primary goal of the current project is thus to characterize the roles of P2X7 and TRPM2 during the early events of T cell activation. To this end, we will use live cell Ca2+ and ATP imaging, HPLC, and patch-clamp techniques to study the roles of these channels in TCR signaling. Especially, we will test the hypothesis that 2-deoxy-adenosine diphosphoribose (2-deoxy-ADPR), instead of ADPR, is the major endogenous activating ligand of TRPM2. Further, we will characterize TCR- and P2X7-induced release of ATP, its localization in relation to the immunological synapse, and its relevance for T-cell activation, thereby providing a link between the worlds of signaling by intra- and extracellular nucleotides. Characterization of the roles of P2X7 and TRPM2 in TCR signaling will provide the basis for assessing the potential of new therapeutic strategies aimed at targeting these two ion channels.

P2X7和TRPM2是T淋巴细胞表达的阳离子通道，分别由胞外和胞内腺嘌呤核苷酸门控。尽管越来越多的证据表明这两种通道在炎症中发挥了关键作用，但它们对T细胞的影响仍不清楚。因此，本项目的主要目标是确定P2X7和TRPM2在T细胞激活的早期事件中的作用。为此，我们将使用活细胞钙离子和三磷酸腺苷成像、高效液相色谱和膜片钳技术来研究这些通道在TCR信号转导中的作用。特别是，我们将检验这一假设，即2-脱氧腺苷二磷酸核糖(2-deoxy-ADPR)而不是ADPR是TRPM2的主要内源性激活配体。此外，我们将表征TCR和P2X7诱导的ATP释放，它与免疫突触的定位，以及它与T细胞激活的相关性，从而在细胞内和细胞外核苷酸的信号世界之间提供联系。确定P2X7和TRPM2在TCR信号中的作用将为评估针对这两个离子通道的新治疗策略的潜力提供基础。

项目成果

The Multiple Roles of ATP-Gated P2(X) Ion Channels in T Lymphocytes

T 淋巴细胞中 ATP 门控 P2(X) 离子通道的多重作用

• DOI: 10.1166/msr.2015.1046
• 发表时间: 2015
• 期刊: The Messenger
• 作者: Haag F;Menzel S;Javed S;Rissiek A;Adriouch S;Tolosa E;Koch-Nolte F
• 通讯作者: Koch-Nolte F

Using FRET-Based Fluorescent Sensors to Monitor Cytosolic and Membrane-Proximal Extracellular ATP Levels.

使用基于 FRET 的荧光传感器监测细胞溶质和近膜细胞外 ATP 水平

• DOI: 10.1007/978-1-4939-9717-6_16
• 发表时间: 2020
• 期刊: Methods in molecular biology
• 作者: Kaschubowski KE;Kraft AE;Nikolaev VO;Haag F
• 通讯作者: Haag F

P2X7-mediated ATP secretion is accompanied by depletion of cytosolic ATP

• DOI: 10.1007/s11302-019-09654-5
• 发表时间: 2019-06-01
• 期刊: PURINERGIC SIGNALLING
• 影响因子: 3.5
• 作者: Johnsen, Bjarne;Kaschubowski, Klaus Eric;Haag, Friedrich
• 通讯作者: Haag, Friedrich