Complexin controls spontaneous and evoked neurotransmitter release by regulating the timing and properties of synaptotagmin activity.
Complexin controls spontaneous and evoked neurotransmitter release by regulating the timing and properties of synaptotagmin activity.
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DOI：
10.1523/jneurosci.3212-12.2012
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发表时间：
2012-12-12
期刊：
影响因子：
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通讯作者：
Littleton JT
中科院分区：
文献类型：
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作者：
Jorquera RA;Huntwork-Rodriguez S;Akbergenova Y;Cho RW;Littleton JT
突触囊泡（synaptic vesicle，SV）融合后神经递质的释放是神经元通讯的基本机制。突触胞吐作用是细胞间通讯的一种特殊形式，与其他膜运输途径共享共同的SNARE介导的融合机制。突触囊泡融合动力学和短时程可塑性的调节对于突触间信号的快速编码和传递至关重要。SNARE结合蛋白的几个家族已经进化为调节突触胞吐作用，包括突触结合蛋白（SYT）和复合蛋白（CPX）。在这里，我们表明，果蝇CPX控制诱发融合发生通过同步和异步途径。cpx−/−突变体显示增加的异步释放，而CPX过表达在很大程度上消除了融合的异步成分。我们还发现，SYT和CPX共调节神经递质释放的动力学和Ca ~（2+）协同性。CPX部分地通过将Ca 2+传感器SYT耦合到融合机器并使其活性同步以加速融合而起释放的正调节剂的作用。相反，syt−/−; cpx−/−双突变体完全消除了单独cpx−/−突变体中观察到的增强的自发释放，表明CPX作为融合钳，部分通过防止SYT对SNARE机制的不适当激活来阻断过早的胞吐作用。CPX水平还控制突触囊泡池的大小，包括立即可释放池和准备可释放池-短期可塑性的关键要素，其定义了突触在突发放电期间维持反应的能力。这些观察结果表明，CPX调节自发和诱发的融合，通过调节突触囊泡周期期间SYT激活的时间和性质。
Neurotransmitter release following synaptic vesicle (SV) fusion is the fundamental mechanism for neuronal communication. Synaptic exocytosis is a specialized form of intercellular communication that shares a common SNARE-mediated fusion mechanism with other membrane trafficking pathways. The regulation of synaptic vesicle fusion kinetics and short-term plasticity is critical for rapid encoding and transmission of signals across synapses. Several families of SNARE-binding proteins have evolved to regulate synaptic exocytosis, including Synaptotagmin (SYT) and Complexin (CPX). Here we demonstrate that Drosophila CPX controls evoked fusion occurring via the synchronous and asynchronous pathways. cpx−/− mutants show increased asynchronous release, while CPX overexpression largely eliminates the asynchronous component of fusion. We also find that SYT and CPX co-regulate the kinetics and Ca2+ cooperativity of neurotransmitter release. CPX functions as a positive regulator of release in part by coupling the Ca2+ sensor SYT to the fusion machinery and synchronizing its activity to speed fusion. In contrast, syt−/−; cpx−/− double mutants completely abolish the enhanced spontaneous release observe in cpx−/− mutants alone, indicating CPX acts as a fusion clamp to block premature exocytosis in part by preventing inappropriate activation of the SNARE machinery by SYT. CPX levels also control the size of synaptic vesicle pools, including the immediate releasable pool and the ready releasable pool – key elements of short-term plasticity that define the ability of synapses to sustain responses during burst firing. These observations indicate CPX regulates both spontaneous and evoked fusion by modulating the timing and properties of SYT activation during the synaptic vesicle cycle.