Synaptotagmin 7 docks synaptic vesicles for Doc2α -triggered asynchronous neurotransmitter release
Synaptotagmin 7 docks synaptic vesicles for Doc2α -triggered asynchronous neurotransmitter release
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发表时间：
2022
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通讯作者：
Zhenyong Wu;Grant F. Kusick;S. Raychaudhuri;Kie Itoh;R. Edwin;Chapman;Shigeki Watanabe
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作者：
Zhenyong Wu;Grant F. Kusick;S. Raychaudhuri;Kie Itoh;R. Edwin;Chapman;Shigeki Watanabe
尽管经过几十年的深入研究，神经递质异步释放的分子基础仍然是个谜。Synaptotagmin（syt）7和Doc2都被认为是触发这种胞吐模式的Ca 2+传感器，但相互矛盾的发现导致了争议。在这里，我们证明，在兴奋性小鼠海马突触，Doc2α是主要的钙2+传感器异步释放，而syt7支持这一过程，通过活动依赖性对接的突触囊泡。在缺乏Doc2α的突触中，单个动作电位后的异步释放强烈减少，而删除syt7则没有影响。然而，在缺乏syt7的情况下，停靠的囊泡不能在毫秒级的时间尺度上恢复。因此，在重复活动期间，同步和异步释放都从第二个脉冲开始抑制。相比之下，缺乏Doc2α的突触具有正常的活动依赖性对接，但在多次刺激后继续表现出减少的异步释放。此外，这两个Ca 2+传感器的破坏是非加性的。这些发现导致了一种新的模型，其中syt7驱动活动依赖性对接，从而“喂养”突触囊泡到Doc2，以便在正在进行的传输过程中异步释放。
The molecular basis of asynchronous neurotransmitter release remains enigmatic despite decades of intense study. Synaptotagmin (syt) 7 and Doc2 have both been proposed as Ca 2+ sensors that trigger this mode of exocytosis, but conflicting findings have led to controversy. Here, we demonstrate that at excitatory mouse hippocampal synapses, Doc2α is the major Ca 2+ sensor for asynchronous release, while syt7 supports this process through activity-dependent docking of synaptic vesicles. In synapses lacking Doc2α, asynchronous release after single action potentials is strongly reduced, while deleting syt7 has no effect. However, in the absence of syt7, docked vesicles cannot recover on millisecond timescales. Consequently, both synchronous and asynchronous release depress from the second pulse on during repetitive activity. By contrast, synapses lacking Doc2α have normal activity -dependent docking, but continue to exhibit decreased asynchronous release after multiple stimuli. Moreover, disruption of both Ca 2+ sensors is non-additive. These findings result in a new model whereby syt7 drives activity-dependent docking, thus ‘feeding’ synaptic vesicles to Doc2 for asynchronous release during on-going transmission.