Coupling the Structural and Functional Assembly of Synaptic Release Sites.
Coupling the Structural and Functional Assembly of Synaptic Release Sites.
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DOI：
10.3389/fnana.2018.00081
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发表时间：
2018
影响因子：
2.9
通讯作者：
Sigrist SJ
中科院分区：
文献类型：
--
作者：
Ghelani T;Sigrist SJ
我们大脑中的信息处理取决于钙 (Ca2+) 激活的突触小泡 (SV) 胞吐作用从嵌入突触前活动区 (AZ) 内的独特释放位点的准确时间。虽然AZ支架蛋白显然为释放位点功能提供了有效的环境，但创建此类释放位点的分子设计长期以来仍然未知。突触前蛋白结构超微结构和拓扑可视化的最新进展已经开始阐明支架蛋白如何建立“纳米结构域”，在物理和功能上将电压门控 Ca2+ 通道 (VGCC) 与可释放的 SV 连接起来。这里的支架蛋白似乎充当“分子标尺或间隔物”，将 SV-VGCC 物理距离调节在数十纳米范围内，从而影响 SV 释放的概率和可塑性。最近对果蝇和哺乳动物突触的多项研究表明，专性释放因子 (M)Unc13 的离散簇的稳定定位定义了 SV 释放位点的位置，并且 (M)Unc13 亚型在突触处的差异表达可以调节 SV-VGCC 偶联。我们在这里回顾成熟的 AZ 支架的组织，了解其内在组织和释放位点形成的作用。此外，我们还讨论了对 AZ 组装发育顺序的见解，这通常需要 VGCC 和 SV 释放位点之间的紧密结合。这里讨论的研究结果取自脊椎动物和无脊椎动物制剂，包括从细胞生物学、超分辨率光学和电子显微镜到生物物理和电生理学分析的一系列方法。我们对突触前 AZ 的结构和功能组织如何耦合的理解已经成熟，因为这些过程对于理解突触成熟和可塑性以及化学突触的准确信息传递和存储至关重要。
Information processing in our brains depends on the exact timing of calcium (Ca2+)-activated exocytosis of synaptic vesicles (SVs) from unique release sites embedded within the presynaptic active zones (AZs). While AZ scaffolding proteins obviously provide an efficient environment for release site function, the molecular design creating such release sites had remained unknown for a long time. Recent advances in visualizing the ultrastructure and topology of presynaptic protein architectures have started to elucidate how scaffold proteins establish “nanodomains” that connect voltage-gated Ca2+ channels (VGCCs) physically and functionally with release-ready SVs. Scaffold proteins here seem to operate as “molecular rulers or spacers,” regulating SV-VGCC physical distances within tens of nanometers and, thus, influence the probability and plasticity of SV release. A number of recent studies at Drosophila and mammalian synapses show that the stable positioning of discrete clusters of obligate release factor (M)Unc13 defines the position of SV release sites, and the differential expression of (M)Unc13 isoforms at synapses can regulate SV-VGCC coupling. We here review the organization of matured AZ scaffolds concerning their intrinsic organization and role for release site formation. Moreover, we also discuss insights into the developmental sequence of AZ assembly, which often entails a tightening between VGCCs and SV release sites. The findings discussed here are retrieved from vertebrate and invertebrate preparations and include a spectrum of methods ranging from cell biology, super-resolution light and electron microscopy to biophysical and electrophysiological analysis. Our understanding of how the structural and functional organization of presynaptic AZs are coupled has matured, as these processes are crucial for the understanding of synapse maturation and plasticity, and, thus, accurate information transfer and storage at chemical synapses.
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