Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol
Dynamic NHERF interaction with TRPC4/5 proteins is required for channel gating by diacylglycerol
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DOI：
10.1073/pnas.1612263114
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发表时间：
2017-01-03
影响因子：
11.1
通讯作者：
Gudermann, Thomas
中科院分区：
文献类型：
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作者：
Storch, Ursula;Forst, Anna-Lena;Gudermann, Thomas
经典瞬时受体电位通道TRPC4和-5通过G（q/11）蛋白-磷脂酶C （PLC）信号通路的激活机制至今仍不清楚。与所有其他TRPC通道相比，PLC产物二酰基甘油（DAG）不足以激活通道，而TRPC4/5通道的活性通过磷脂酰肌醇4,5-二磷酸（PIP2）的消耗而增强。作为一个典型的结构特征，TRPC4/5通道包含一个c端pdz结合基元，允许结合支架蛋白Na+/H+交换调节因子（NHERF） 1和2。PKC抑制或c端pdz结合基序中苏氨酸交换丙氨酸赋予DAG对通道的敏感性。总之，我们提出了由dag介导的TRPC4/5通道的激活机制，该机制受到NHERF1/2相互作用的严格调控。PIP2缺失引起TRPC5蛋白的C端构象改变，导致NHERF1/2从TRPC5的C端动态解离，这是DAG敏感性的先决条件。我们发现NHERF蛋白是离子通道活性的直接调节剂，而DAG敏感性是TRPC通道的独特标志。
The activation mechanism of the classical transient receptor potential channels TRPC4 and -5 via the G(q/11) protein-phospholipase C (PLC) signaling pathway has remained elusive so far. In contrast to all other TRPC channels, the PLC product diacylglycerol (DAG) is not sufficient for channel activation, whereas TRPC4/5 channel activity is potentiated by phosphatidylinositol 4,5-bisphosphate (PIP2) depletion. As a characteristic structural feature, TRPC4/5 channels contain a C-terminal PDZ-binding motif allowing for binding of the scaffolding proteins Na+/H+ exchanger regulatory factor (NHERF) 1 and 2. PKC inhibition or the exchange of threonine for alanine in the C-terminal PDZ-binding motif conferred DAG sensitivity to the channel. Altogether, we present a DAG-mediated activation mechanism for TRPC4/5 channels tightly regulated by NHERF1/2 interaction. PIP2 depletion evokes a C-terminal conformational change of TRPC5 proteins leading to dynamic dissociation of NHERF1/2 from the C terminus of TRPC5 as a prerequisite for DAG sensitivity. We show that NHERF proteins are direct regulators of ion channel activity and that DAG sensitivity is a distinctive hallmark of TRPC channels.