PICK1 控制活性依赖的突触囊泡货物回收。

PICK1 Controls Activity-Dependent Synaptic Vesicle Cargo Retrieval.

机构信息

Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia.

Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, Scotland, UK; Muir Maxwell Epilepsy Centre, University of Edinburgh, Edinburgh EH8 9XD, Scotland, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh EH8 9XD, Scotland, UK.

出版信息

Cell Rep. 2020 Oct 27;33(4):108312. doi: 10.1016/j.celrep.2020.108312.

DOI:10.1016/j.celrep.2020.108312

PMID:33113376

Abstract

Efficient retrieval of synaptic vesicles (SVs) is crucial to sustain synaptic transmission. Protein interacting with C-kinase 1 (PICK1) is a unique PDZ (postsynaptic density-95/disc-large/zona-occluden-1)- and BAR (Bin-Amphiphysin-Rvs )-domain-containing protein that regulates the trafficking of postsynaptic glutamate receptors. It is also expressed in presynaptic terminals and is associated with the SVs; however, its role in regulating SV recycling remains unknown. Here, we show that PICK1 loss of function selectively slows the kinetics of SV endocytosis in primary hippocampal neurons during high-frequency stimulation. PICK1 knockdown also causes surface stranding and mislocalization of major SV proteins, synaptophysin and vGlut1, along the axon. A functional PDZ domain of PICK1 and its interaction with the core endocytic adaptor protein (AP)-2 are required for the proper targeting and clustering of synaptophysin. Furthermore, PICK1 and its interaction with AP-2 are required for efficient SV endocytosis and sustained glutamate release. Our findings, therefore, identify PICK1 as a key regulator of presynaptic vesicle recycling in central synapses.

摘要

有效回收突触小泡（SVs）对于维持突触传递至关重要。蛋白相互作用激酶 1（PICK1）是一种独特的 PDZ（突触后密度-95/离散大/zona-occluden-1）和 BAR（Bin-Amphiphysin-Rvs）域蛋白，它调节突触后谷氨酸受体的运输。它也在突触前末端表达，并与 SVs 相关联；然而，其在调节 SV 再循环中的作用尚不清楚。在这里，我们表明 PICK1 功能丧失选择性地在高频刺激期间减缓原代海马神经元中 SV 内吞的动力学。PICK1 敲低还导致主要 SV 蛋白突触小体和 vGlut1 沿着轴突的表面缠结和定位错误。PICK1 的功能性 PDZ 结构域及其与核心内吞衔接蛋白（AP）-2 的相互作用对于突触小体的正确靶向和聚类是必需的。此外，PICK1 及其与 AP-2 的相互作用对于有效的 SV 内吞作用和持续的谷氨酸释放是必需的。因此，我们的发现确定 PICK1 是中枢突触中 SV 再循环的关键调节因子。