Role of activation of PIP5Kγ661 by AP-2 complex in synaptic vesicle endocytosis
Role of activation of PIP5Kγ661 by AP-2 complex in synaptic vesicle endocytosis
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DOI：
10.1038/sj.emboj.7601573
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发表时间：
2007-02-21
期刊：
影响因子：
11.4
通讯作者：
Kanaho, Yasunori
中科院分区：
文献类型：
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作者：
Nakano-Kobayashi, Akiko;Yamazaki, Masakazu;Kanaho, Yasunori
突触囊泡（SV）是通过网格蛋白介导的内吞作用在神经末梢回收的。磷脂酰肌醇4，5-二磷酸[PI（4，5）P-2]通过募集内吞机制的组分来驱动该事件。然而，导致PI（4，5）P-2局部产生的分子机制仍不清楚。我们在这里证明，AP-2复合物直接相互作用与磷脂酰肌醇4-磷酸5-激酶γ 661（PIP 5 Kc 661），主要的PI（4，5）P-2生产酶在大脑中。发现AP-2的β 2亚基与PIP 5 Kc 661的C-末端尾结合并引起PIP 5 Kc 661活化。这种相互作用受PIP 5 Kc 661去磷酸化的调节，PIP 5 Kc 661去磷酸化是由小鼠海马神经元的去极化触发的。最后，海马神经元中PIP 5 Kc 661 C-末端区域的过表达抑制去极化依赖性SV内吞作用。这些发现为PIP 5 Kc 661在海马神经元中局部产生PI（4，5）P-2的分子机制提供了证据，并提出了相互作用触发SV内吞的模型。
Synaptic vesicles (SVs) are retrieved by clathrin-mediated endocytosis at the nerve terminals. Phosphatidylinositol 4,5-bisphosphate [PI( 4,5) P-2] drives this event by recruiting the components of the endocytic machinery. However, the molecular mechanisms that result in local generation of PI( 4,5) P-2 remain unclear. We demonstrate here that AP-2 complex directly interacts with phosphatidylinositol 4-phosphate 5-kinase gamma 661 (PIP5Kc661), the major PI(4,5) P-2-producing enzyme in the brain. The beta 2 subunit of AP-2 was found to bind to the C-terminal tail of PIP5Kc661 and cause PIP5Kc661 activation. The interaction is regulated by PIP5Kc661 dephosphorylation, which is triggered by depolarization in mouse hippocampal neurons. Finally, overexpression of the PIP5Kc661 C-terminal region in hippocampal neurons suppresses depolarization-dependent SV endocytosis. These findings provide evidence for the molecular mechanism through which PIP5Kc661 locally generates PI( 4,5) P-2 in hippocampal neurons and suggest a model in which the interaction trigger SV endocytosis.