A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release.
A novel dual Ca2+ sensor system regulates Ca2+-dependent neurotransmitter release.
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DOI：
10.1083/jcb.202008121
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发表时间：
2021-04-05
期刊：
影响因子：
--
通讯作者：
Hu Z
中科院分区：
文献类型：
--
作者：
Li L;Liu H;Krout M;Richmond JE;Wang Y;Bai J;Weeratunga S;Collins BM;Ventimiglia D;Yu Y;Xia J;Tang J;Liu J;Hu Z
Li等人发现SNT-1和SNT-3是触发秀丽隐杆线虫神经肌肉连接处突触囊泡Ca2+依赖性胞外分泌的主要和次要Ca2+传感器。这两种Ca2+传感器表现出不同的结构域结构和轴突分布，并介导具有不同突触特性的突触囊泡释放。Ca2+依赖性神经递质释放需要synaptotagmins作为Ca2+传感器，通过其串联C2结构域- c2a和c2b -与Ca2+结合来触发突触囊泡（SV）胞外分泌。我们之前已经证明了SNT-1，一个小鼠突触蛋白-1 （Syt1）同源物，在秀丽隐杆线虫中作为快速Ca2+传感器起作用。在这里，我们报告了一个新的Ca2+传感器，SNT-3，它触发延迟Ca2+依赖的神经递质释放。snt-1;snt-3双突变体消除了诱发的突触传递，表明秀丽隐杆线虫NMJs使用双Ca2+传感器系统。SNT-3在两个C2结构域都具有典型的天冬氨酸残基，但缺乏一个n端跨膜结构域。生化证据表明，SNT-3结合Ca2+和质膜。功能分析表明，当SNT-1功能受损时，SNT-3被激活，触发与Ca2+进入松散耦合的SV释放。SNT-1与SV相关，而SNT-3与SV无关。通过去除TM结构域或整个N端来消除SNT-1的SV系结可以恢复快速释放动力学，这表明细胞质SNT-1仍然具有功能并触发快速神经递质释放，但也表现出诱发振幅和释放概率的降低。这些结果表明SV释放的快慢特性是由SNT-1和SNT-3内在不同的C2结构域决定的，而不是由它们的n端介导的膜系固作用决定的。因此，我们的研究结果揭示了秀丽隐杆线虫中一种新的双Ca2+传感器系统，并为Ca2+调节的胞吐作用提供了重要的见解。
Li et al. identify SNT-1 and SNT-3 as the primary and secondary Ca2+ sensors that trigger Ca2+-dependent exocytosis of synaptic vesicles at the Caenorhabditis elegans neuromuscular junction. These two Ca2+ sensors display differential domain structure and axonal distribution, and mediate synaptic vesicle release with different synaptic properties. Ca2+-dependent neurotransmitter release requires synaptotagmins as Ca2+ sensors to trigger synaptic vesicle (SV) exocytosis via binding of their tandem C2 domains—C2A and C2B—to Ca2+. We have previously demonstrated that SNT-1, a mouse synaptotagmin-1 (Syt1) homologue, functions as the fast Ca2+ sensor in Caenorhabditis elegans. Here, we report a new Ca2+ sensor, SNT-3, which triggers delayed Ca2+-dependent neurotransmitter release. snt-1;snt-3 double mutants abolish evoked synaptic transmission, demonstrating that C. elegans NMJs use a dual Ca2+ sensor system. SNT-3 possesses canonical aspartate residues in both C2 domains, but lacks an N-terminal transmembrane (TM) domain. Biochemical evidence demonstrates that SNT-3 binds both Ca2+ and the plasma membrane. Functional analysis shows that SNT-3 is activated when SNT-1 function is impaired, triggering SV release that is loosely coupled to Ca2+ entry. Compared with SNT-1, which is tethered to SVs, SNT-3 is not associated with SV. Eliminating the SV tethering of SNT-1 by removing the TM domain or the whole N terminus rescues fast release kinetics, demonstrating that cytoplasmic SNT-1 is still functional and triggers fast neurotransmitter release, but also exhibits decreased evoked amplitude and release probability. These results suggest that the fast and slow properties of SV release are determined by the intrinsically different C2 domains in SNT-1 and SNT-3, rather than their N-termini–mediated membrane tethering. Our findings therefore reveal a novel dual Ca2+ sensor system in C. elegans and provide significant insights into Ca2+-regulated exocytosis.
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