Intersectin associates with synapsin and regulates its nanoscale localization and function
Intersectin associates with synapsin and regulates its nanoscale localization and function
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DOI：
10.1073/pnas.1715341114
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发表时间：
2017-11-07
影响因子：
11.1
通讯作者：
Haucke, Volker
中科院分区：
文献类型：
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作者：
Gerth, Fabian;Jaepel, Maria;Haucke, Volker
神经传递是由活跃区易释放突触囊泡（SVs）的神经递质胞外释放介导的。为了在活动升高期间维持神经传递，需要从sv储备池中补充准备释放的囊泡。与sv相关的突触对于维持这一储备池和调节储备池sv的动员至关重要。释放就绪的sv是如何从储备池中补充调节的，以及在这一过程中有哪些其他因素与突触协同作用尚不清楚。在这里，我们发现内吞多结构域支架蛋白交叉蛋白是海马突触SV补充的重要调节因子。我们发现，交叉蛋白通过其src同源的3a结构域直接与突触蛋白I结合，这种结合是由交叉蛋白1的分子内开关调节的。小鼠中相交蛋白1/2的缺失会改变突触蛋白1的突触前纳米级分布，并由于SV补充缺陷导致持续神经传递缺陷。这些表型是由野生型交叉蛋白1拯救的，而不是由交叉蛋白1的锁定突变体拯救的。我们的数据显示交叉蛋白是一种自抑制支架，作为突触蛋白依赖储备池和突触前内吞机制之间的分子连接物。
Neurotransmission is mediated by the exocytic release of neuro-transmitters from readily releasable synaptic vesicles (SVs) at the active zone. To sustain neurotransmission during periods of elevated activity, release-ready vesicles need to be replenished from the reserve pool of SVs. The SV-associated synapsins are crucial for maintaining this reserve pool and regulate the mobilization of reserve pool SVs. How replenishment of release-ready SVs from the reserve pool is regulated and which other factors cooperate with synapsins in this process is unknown. Here we identify the endocytic multidomain scaffold protein intersectin as an important regulator of SV replenishment at hippocampal synapses. We found that intersectin directly associates with synapsin I through its Src-homology 3 A domain, and this association is regulated by an intramolecular switch within intersectin 1. Deletion of intersectin 1/2 in mice alters the presynaptic nanoscale distribution of synapsin I and causes defects in sustained neurotransmission due to defective SV replenishment. These phenotypes were rescued by wild-type intersectin 1 but not by a locked mutant of intersectin 1. Our data reveal intersectin as an autoinhibited scaffold that serves as a molecular linker between the synapsin-dependent reserve pool and the presynaptic endocytosis machinery.