Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement
Elucidation of a TRPC6-TRPC5 channel cascade that restricts endothelial cell movement
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DOI：
10.1091/mbc.e07-08-0765
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Graham, Linda M.
中科院分区：
文献类型：
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作者：
Chaudhuri, Pinaki;Colles, Scott M.;Graham, Linda M.
经典瞬时受体电位（TRPC）通道是由受体激活或细胞内钙库耗竭引发的经典信号转导事件打开的。在这里，我们报告了一种新的机制，开放TRPC通道，其中TRPC 6激活启动级联导致TRPC 5易位。当内皮细胞（EC）在溶血磷脂酰胆碱（lysoPC）中孵育时，TRPC 6的快速易位启动钙内流，导致TRPC 5的外化。该TRPC 6 -5级联反应的激活导致细胞内钙浓度（[Ca 2 +]（i））长期增加，从而抑制EC运动。当TRPC 5被siRNA下调时，lysoPC诱导的[Ca 2 +]（i）升高缩短，EC迁移的抑制减轻。当TRPC 6下调或研究来自TRPC 6（-/-）小鼠的EC时，lysoPC对[Ca 2 +]（i）和EC迁移的影响最小。此外，TRPC 5不响应于lysoPC而外化，支持TRPC 5易位依赖于TRPC 6通道的开放。这种新的TRPC通道级联激活的lysoPC，导致EC迁移的抑制，可能会对EC愈合的动脉粥样硬化动脉中的lysoPC是丰富的不利影响。
Canonical transient receptor potential (TRPC) channels are opened by classical signal transduction events initiated by receptor activation or depletion of intracellular calcium stores. Here, we report a novel mechanism for opening TRPC channels in which TRPC6 activation initiates a cascade resulting in TRPC5 translocation. When endothelial cells (ECs) are incubated in lysophosphatidylcholine (lysoPC), rapid translocation of TRPC6 initiates calcium influx that results in externalization of TRPC5. Activation of this TRPC6-5 cascade causes a prolonged increase in intracellular calcium concentration ([Ca2+](i)) that inhibits EC movement. When TRPC5 is down-regulated with siRNA, the lysoPC-induced rise in [Ca2+](i) is shortened and the inhibition of EC migration is lessened. When TRPC6 is down-regulated or EC from TRPC6(-/-)mice are studied, lysoPC has minimal effect on [Ca2+](i) and EC migration. In addition, TRPC5 is not externalized in response to lysoPC, supporting the dependence of TRPC5 translocation on the opening of TRPC6 channels. Activation of this novel TRPC channel cascade by lysoPC, resulting in the inhibition of EC migration, could adversely impact on EC healing in atherosclerotic arteries where lysoPC is abundant.