Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles.
Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles.
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DOI：
10.1038/ncomms15915
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发表时间：
2017-06-21
影响因子：
16.6
通讯作者：
Verhage M
中科院分区：
文献类型：
--
作者：
He E;Wierda K;van Westen R;Broeke JH;Toonen RF;Cornelisse LN;Verhage M
突触传递需要一个稳定的释放准备(启动)囊泡池。在这里，我们展示了参与SNARE-Complex组装的两个分子，Munc13-1和Munc18-1，通过防止去启动来共同稳定释放准备就绪的囊泡。用非神经元异构体Munc18-2(Munc18-1/2SWAP)取代神经元Munc18-1支持活动依赖的启动，但启动的囊泡在几秒钟内回到不可释放的状态(去质数)。Munc13-1缺乏也会产生类似的缺陷。N-乙基马来酰亚胺敏感因子(NSF)、N-乙基马来酰亚胺(NEM)或干扰肽的抑制剂可以阻止Munc18-1/2SWAP或Munc13-1零突触的去引爆，但对另一个启动缺陷突变体Caps-1/2 Null却不起作用。NEM可挽救Munc13-1 Null和Munc18-1/2SWAP突触、急性Munc13-1 Null切片甚至部分Munc13-1/2双Null突触的突触传递。总之，这些数据表明，Munc13-1和Munc18-1，而不是Caps-1/2，通过防止NSF依赖的去启动来稳定预启动的突触小泡。由启动的突触小泡组成的易释放池的产生和维持的分子机制只有部分知道。在这里，作者表明，在小鼠的初级神经元中，Munc13-1和Munc18-1通过阻止NSF依赖的去启动来稳定被启动的突触小泡。
Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming. The molecular mechanism underlying the generation and maintenance of the readily releasable pool composed of primed synaptic vesicles is only partially known. Here the authors show that in mouse primary neurons, Munc13-1 and Munc18-1 stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.