组胺的合成和运输在轴突末端通过双重质量控制系统耦合在一起。

IF 9.4 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
EMBO Journal Pub Date : 2024-10-01 Epub Date: 2024-09-06 DOI:10.1038/s44318-024-00223-0
Lei Peng, Tao Wang
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引用次数: 0

摘要

通过新合成产生的单胺类神经递质会被迅速转运并储存到轴突末端的突触小泡中。这种转运对于维持突触传递和限制单胺类神经递质的毒性作用至关重要。在这里,组氨酸脱羧酶(HDC)合成单胺组胺以及随后将组胺装入突触小泡的过程被证明在果蝇感光器末端是物理和功能耦合的。这一过程需要 HDC 通过与 N-乙基马来酰亚胺敏感融合蛋白 1(NSF1)的相互作用锚定在突触小泡上。将 HDC 从突触小泡中分离出来会破坏视觉突触传递,并导致组胺在体表蓄积,从而导致视网膜变性。我们进一步发现了一个由 E3 泛素连接酶纯度(POE)介导的蛋白酶体降解系统,它能清除体细胞中错误定位的 HDC,从而消除组胺的细胞毒性作用。综上所述,我们的研究结果揭示了组胺转运和降解的双重机制,它既能确保组胺的合成限制在轴突末端,又能确保组胺快速进入突触小泡。这对于维持神经传递和抵御细胞毒性单胺类物质至关重要。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Histamine synthesis and transport are coupled in axon terminals via a dual quality control system.

Monoamine neurotransmitters generated by de novo synthesis are rapidly transported and stored into synaptic vesicles at axon terminals. This transport is essential both for sustaining synaptic transmission and for limiting the toxic effects of monoamines. Here, synthesis of the monoamine histamine by histidine decarboxylase (HDC) and subsequent loading of histamine into synaptic vesicles are shown to be physically and functionally coupled within Drosophila photoreceptor terminals. This process requires HDC anchoring to synaptic vesicles via interactions with N-ethylmaleimide-sensitive fusion protein 1 (NSF1). Disassociating HDC from synaptic vesicles disrupts visual synaptic transmission and causes somatic accumulation of histamine, which leads to retinal degeneration. We further identified a proteasome degradation system mediated by the E3 ubiquitin ligase, purity of essence (POE), which clears mislocalized HDC from the soma, thus eliminating the cytotoxic effects of histamine. Taken together, our results reveal a dual mechanism for translocation and degradation of HDC that ensures restriction of histamine synthesis to axonal terminals and at the same time rapid loading into synaptic vesicles. This is crucial for sustaining neurotransmission and protecting against cytotoxic monoamines.

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来源期刊
EMBO Journal
EMBO Journal 生物-生化与分子生物学
CiteScore
18.90
自引率
0.90%
发文量
246
审稿时长
1.5 months
期刊介绍: The EMBO Journal has stood as EMBO's flagship publication since its inception in 1982. Renowned for its international reputation in quality and originality, the journal spans all facets of molecular biology. It serves as a platform for papers elucidating original research of broad general interest in molecular and cell biology, with a distinct focus on molecular mechanisms and physiological relevance. With a commitment to promoting articles reporting novel findings of broad biological significance, The EMBO Journal stands as a key contributor to advancing the field of molecular biology.
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