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RIM和MUNC13膜结合结构域对神经肽分泌至关重要。

RIM and MUNC13 membrane-binding domains are essential for neuropeptide secretion.

作者信息

Murphy Fiona H, Abramian Adlin, Klaassen Remco V, Koopmans Frank, Persoon Claudia M, Smit August B, Toonen Ruud F, Verhage Matthijs

机构信息

Department of Human Genetics, Center for Neurogenomics and Cognitive Research (CNCR), Amsterdam University Medical Center (UMC), Amsterdam, Netherlands.

Department of Functional Genomics, Vrije Universiteit (VU) Amsterdam, Amsterdam, Netherlands.

出版信息

J Cell Biol. 2025 Jul 7;224(7). doi: 10.1083/jcb.202409196. Epub 2025 May 12.

DOI:10.1083/jcb.202409196
PMID:40353777
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12077229/
Abstract

Neurons release neurotransmitters from synaptic vesicles (SVs) and neuropeptides from dense-core vesicles (DCVs). The presynaptic proteins RIM and MUNC13 play key roles in both pathways. It remains unclear how DCVs are targeted to release sites and whether RIM and MUNC13 are involved in this process. Here, we show that three membrane-binding domains in RIM and MUNC13 regulate DCV exocytosis differently from SV exocytosis. Using neuropeptide secretion assays with single-vesicle resolution and peptidomics analysis of endogenous neuropeptide release in MUNC13/RIM null neurons, we demonstrate that MUNC13 is essential for DCV exocytosis. The RIM N terminus prevents MUNC13 degradation via the proteasome, and inhibiting proteasomal degradation partially rescues DCV exocytosis in RIM's absence. Unlike SV exocytosis, the PIP2-binding RIM C2B domain and MUNC13 C1-C2B polybasic face are redundant for DCV exocytosis, while the lipid-binding MUNC13 C2C domain is crucial. These results show that RIM and MUNC13 synergistically regulate DCV exocytosis through membrane interactions and reveal new mechanistic differences between SV and DCV exocytosis.

摘要

神经元从突触小泡（SVs）释放神经递质，从致密核心小泡（DCVs）释放神经肽。突触前蛋白RIM和MUNC13在这两个途径中都起着关键作用。目前尚不清楚DCVs如何靶向释放位点，以及RIM和MUNC13是否参与这一过程。在这里，我们表明RIM和MUNC13中的三个膜结合结构域对DCV胞吐作用的调节方式与SV胞吐作用不同。使用具有单小泡分辨率的神经肽分泌测定法以及对MUNC13/RIM缺失神经元中内源性神经肽释放的肽组学分析，我们证明MUNC13对DCV胞吐作用至关重要。RIM的N末端可防止MUNC13通过蛋白酶体降解，并且在没有RIM的情况下抑制蛋白酶体降解可部分挽救DCV胞吐作用。与SV胞吐作用不同，结合PIP2的RIM C2B结构域和MUNC13 C1-C2B多碱性面在DCV胞吐作用中是冗余的，而结合脂质的MUNC13 C2C结构域至关重要。这些结果表明，RIM和MUNC13通过膜相互作用协同调节DCV胞吐作用，并揭示了SV和DCV胞吐作用之间新的机制差异。

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Maximal Fusion Capacity and Efficient Replenishment of the Dense Core Vesicle Pool in Hippocampal Neurons.海马神经元中最大融合容量和致密核心囊泡池的有效补充。
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Tomosyn affects dense core vesicle composition but not exocytosis in mammalian neurons.
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Munc13- and SNAP25-dependent molecular bridges play a key role in synaptic vesicle priming.Munc13- 和 SNAP25 依赖性分子桥在突触囊泡引发中起关键作用。
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Munc13 supports fusogenicity of non-docked vesicles at synapses with disrupted active zones.Munc13 支持活性区破坏的突触中非对接小泡的融合。
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