Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics
Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics
复制标题
DOI：
10.1038/nn.4198
复制
发表时间：
2016-02-01
影响因子：
25
通讯作者：
Fakler, Bernd
中科院分区：
文献类型：
--
作者：
Schwenk, Jochen;Perez-Garci, Enrique;Fakler, Bernd
GABA（B）受体是哺乳动物脑中最丰富的抑制性G蛋白偶联受体，在功能特性、细胞信号传导和亚细胞分布方面表现出明显的多样性。我们使用高分辨率功能蛋白质组学来识别啮齿动物大脑中这些受体的构建模块。我们的分析表明，天然GABA（B）受体是具有明确结构的大分子复合物，但亚基组成具有显著的多样性：受体核心由GABA（B1 a/B）、GABA（B2）、四种KCTD蛋白和一组不同的G蛋白亚基组装而成，而受体的外围主要由不同类别的跨膜蛋白形成。特别是，外周形成成分包括信号效应器，如Cav 2和HCN通道，以及蛋白质AJAP 1和淀粉样β A4，两者都与GABA（B1 a）的sushi结构域紧密相关。我们的研究结果揭示了GABAB受体的分子多样性及其出生后的组装动力学，并为研究这种抑制性神经递质受体的细胞信号传导提供了路线图。
GABA(B) receptors, the most abundant inhibitory G protein-coupled receptors in the mammalian brain, display pronounced diversity in functional properties, cellular signaling and subcellular distribution. We used high-resolution functional proteomics to identify the building blocks of these receptors in the rodent brain. Our analyses revealed that native GABA(B) receptors are macromolecular complexes with defined architecture, but marked diversity in subunit composition: the receptor core is assembled from GABA(B1a/b), GABA(B2), four KCTD proteins and a distinct set of G-protein subunits, whereas the receptor's periphery is mostly formed by transmembrane proteins of different classes. In particular, the periphery-forming constituents include signaling effectors, such as Cav2 and HCN channels, and the proteins AJAP1 and amyloid-beta A4, both of which tightly associate with the sushi domains of GABA(B1a). Our results unravel the molecular diversity of GABAB receptors and their postnatal assembly dynamics and provide a roadmap for studying the cellular signaling of this inhibitory neurotransmitter receptor.