Molecular and functional architecture of striatal dopamine release sites.
Molecular and functional architecture of striatal dopamine release sites.
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DOI：
10.1016/j.neuron.2021.10.028
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发表时间：
2022-01-19
期刊：
影响因子：
16.2
通讯作者：
Kaeser PS
中科院分区：
文献类型：
--
作者：
Banerjee A;Imig C;Balakrishnan K;Kershberg L;Lipstein N;Uronen RL;Wang J;Cai X;Benseler F;Rhee JS;Cooper BH;Liu C;Wojcik SM;Brose N;Kaeser PS
尽管多巴胺对纹状体回路功能的重要性，但对多巴胺传递机制的理解仍然不完整。我们最近发现，多巴胺的分泌依赖于突触前支架蛋白RIM，表明它发生在类似于经典的突触囊泡胞吐的活性区样位点。在这里，我们使用系统的基因敲除方法，Munc 13和Liprin-α，囊泡启动和释放位点组织的活性区蛋白，是多巴胺分泌的重要。此外，需要分别与Munc 13和Liprin-α结合的RIM锌指和C2B结构域来恢复RIM消融后的多巴胺释放。相反，与典型的突触不同，活性区骨架RIM-BP和ELKS以及与它们结合的RIM结构域是消耗性的。因此，多巴胺的释放需要RIM、Munc 13和Liprin-α的启动和释放位点支架，但其他活性区蛋白是不可缺少的。我们的工作确立了高效的释放位点结构介导快速多巴胺胞吐。多巴胺是控制纹状体回路功能的关键神经调质。Banerjee，Imig等人表明，诱发的多巴胺分泌发生在含有多个活性区蛋白的释放热点。Munc 13、Liprin-α和RIM协同介导囊泡的启动和释放，而其他已知的活性区蛋白则被抑制。
Despite the importance of dopamine for striatal circuit function, mechanistic understanding of dopamine transmission remains incomplete. We recently showed that dopamine secretion relies on the presynaptic scaffolding protein RIM, indicating that it occurs at active zone-like sites similar to classical synaptic vesicle exocytosis. Here, we establish using a systematic gene knockout approach that Munc13 and Liprin-α, active zone proteins for vesicle priming and release site organization, are important for dopamine secretion. Furthermore, RIM zinc finger and C2B domains, which bind to Munc13 and Liprin-α, respectively, are needed to restore dopamine release after RIM ablation. In contrast, and different from typical synapses, the active zone scaffolds RIM-BP and ELKS, and RIM domains that bind to them, are expendable. Hence, dopamine release necessitates priming and release site scaffolding by RIM, Munc13, and Liprin-α, but other active zone proteins are dispensable. Our work establishes that efficient release site architecture mediates fast dopamine exocytosis. Dopamine is a key neuromodulator for the control of striatal circuit function. Banerjee, Imig et al. show that evoked dopamine secretion occurs at release hotspots that contain multiple active zone proteins. Munc13, Liprin-α, and RIM cooperate to mediate vesicle priming and release, while other known active zone proteins are dispensable.
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影响因子：
16.2
作者：
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