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兴奋性神经肽信号转导的结构基础。

Structural basis for excitatory neuropeptide signaling.

机构信息

Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, the Netherlands.

Department of Biomedicine, University of Bergen, Bergen, Norway.

出版信息

Nat Struct Mol Biol. 2024 Apr;31(4):717-726. doi: 10.1038/s41594-023-01198-y. Epub 2024 Feb 9.

Abstract

Rapid signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning ion channel domain. The degenerin/epithelial sodium channel (DEG/ENaC) superfamily is diverse in terms of its gating stimuli, with some DEG/ENaCs gated by neuropeptides, and others gated by pH, mechanical force or enzymatic activity. The mechanism by which ligands bind to and activate DEG/ENaCs is poorly understood. Here we dissected the structural basis for neuropeptide-gated activity of a neuropeptide-gated DEG/ENaC, FMRFamide-gated sodium channel 1 (FaNaC1) from the annelid worm Malacoceros fuliginosus, using cryo-electron microscopy. Structures of FaNaC1 in the ligand-free resting state and in several ligand-bound states reveal the ligand-binding site and capture the ligand-induced conformational changes of channel gating, which we verified with complementary mutagenesis experiments. Our results illuminate channel gating in DEG/ENaCs and offer a structural template for experimental dissection of channel pharmacology and ion conduction.

摘要

神经元之间的快速信号传递是由配体门控离子通道介导的,配体门控离子通道是一种细胞表面蛋白,具有细胞外配体结合域和跨膜离子通道域。在门控刺激方面,退化素/上皮钠离子通道(DEG/ENaC)超家族具有多样性,一些 DEG/ENaC 由神经肽门控,而另一些则由 pH、机械力或酶活性门控。配体与 DEG/ENaC 结合并激活的机制尚不清楚。在这里,我们使用冷冻电子显微镜技术解析了来自环节蠕虫 Malacoceros fuliginosus 的神经肽门控 DEG/ENaC,即 FMRFamide 门控钠离子通道 1(FaNaC1)的神经肽门控活性的结构基础。FaNaC1 在无配体的静息状态和几种配体结合状态下的结构揭示了配体结合位点,并捕获了通道门控的配体诱导构象变化,我们通过互补突变实验对其进行了验证。我们的研究结果阐明了 DEG/ENaC 的通道门控机制,并为实验解析通道药理学和离子传导提供了结构模板。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/45cb/11026163/e9151423b9ab/41594_2023_1198_Fig1_HTML.jpg

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