The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis.
The trans-SNARE-regulating function of Munc18-1 is essential to synaptic exocytosis.
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DOI：
10.1038/ncomms9852
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发表时间：
2015-11-17
影响因子：
16.6
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Shen C;Rathore SS;Yu H;Gulbranson DR;Hua R;Zhang C;Schoppa NE;Shen J
充满神经递质的突触囊泡与质膜的融合需要两类分子-SNAP受体（SNARE）和Sec 1/Munc 18（SM）蛋白。重构研究表明SM蛋白Munc 18 -1促进trans-SNARE复合物的拉链化，并加速SNARE依赖性膜融合的动力学。然而，这种反式SNARE调节功能在突触胞吐中的生理作用仍有待确定。在这里，我们首先证明了囊泡锚定的v-SNARE中的两个突变选择性地损害Munc 18 -1促进trans-SNARE拉链的能力，而其他已知的Munc 18 -1/SNARE结合模式不受影响。在培养的神经元中，这些v-SNARE突变强烈抑制自发以及诱发的神经递质释放，为Munc 18 -1在突触胞吐中的反式SNARE调节功能提供遗传证据。最后，我们发现Munc 18 -1的反式SNARE调节功能受到与Ohtahara综合征（一种严重形式的癫痫）相关的突变的影响。
The fusion of neurotransmitter-filled synaptic vesicles with the plasma membrane requires two classes of molecules—SNAP receptor (SNARE) and Sec1/Munc18 (SM) protein. Reconstitution studies suggest that the SM protein Munc18-1 promotes the zippering of trans-SNARE complexes and accelerates the kinetics of SNARE-dependent membrane fusion. However, the physiological role of this trans-SNARE-regulating function in synaptic exocytosis remains to be established. Here we first demonstrate that two mutations in the vesicle-anchored v-SNARE selectively impair the ability of Munc18-1 to promote trans-SNARE zippering, whereas other known Munc18-1/SNARE-binding modes are unaffected. In cultured neurons, these v-SNARE mutations strongly inhibit spontaneous as well as evoked neurotransmitter release, providing genetic evidence for the trans-SNARE-regulating function of Munc18-1 in synaptic exocytosis. Finally, we show that the trans-SNARE-regulating function of Munc18-1 is compromised by a mutation associated with Ohtahara Syndrome, a severe form of epilepsy.