Functional implications of the exon 9 splice insert in GluK1 kainate receptors.

IF 6.4 1区 生物学 Q1 BIOLOGY eLife Pub Date : 2024-11-06 DOI:10.7554/eLife.89755
Surbhi Dhingra, Prachi M Chopade, Rajesh Vinnakota, Janesh Kumar
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Abstract

Kainate receptors are key modulators of synaptic transmission and plasticity in the central nervous system. Different kainate receptor isoforms with distinct spatiotemporal expressions have been identified in the brain. The GluK1-1 splice variant receptors, which are abundant in the adult brain, have an extra fifteen amino acids inserted in the amino-terminal domain (ATD) of the receptor resulting from alternative splicing of exon 9. However, the functional implications of this post-transcriptional modification are not yet clear. We employed a multi-pronged approach using cryogenic electron microscopy, electrophysiology, and other biophysical and biochemical tools to understand the structural and functional impact of this splice insert in the extracellular domain of GluK1 receptors. Our study reveals that the splice insert alters the key gating properties of GluK1 receptors and their modulation by the cognate auxiliary Neuropilin and tolloid-like (Neto) proteins 1 and 2. Mutational analysis identified the role of crucial splice residues that influence receptor properties and their modulation. Furthermore, the cryoEM structure of the variant shows that the presence of exon 9 in GluK1 does not affect the receptor architecture or domain arrangement in the desensitized state. Our study thus provides the first detailed structural and functional characterization of GluK1-1a receptors, highlighting the role of the splice insert in modulating receptor properties and their modulation.

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GluK1 kainate 受体第 9 号外显子剪接插入的功能影响。
凯恩酸盐受体是中枢神经系统突触传递和可塑性的关键调节剂。在大脑中已发现不同的凯恩酸受体异构体,它们具有不同的时空表达。在成人大脑中大量存在的 GluK1-1 剪接变体受体,由于外显子 9 的替代剪接,在受体的氨基末端结构域(ATD)中多插入了 15 个氨基酸。然而,这种转录后修饰的功能影响尚不清楚。我们采用低温电子显微镜、电生理学以及其他生物物理和生物化学工具多管齐下的方法来了解 GluK1 受体胞外结构域中这种剪接插入的结构和功能影响。我们的研究发现,该剪接插入物改变了 GluK1 受体的关键门控特性,以及同源辅助神经蛋白和类拓扑(Neto)蛋白 1 和 2 对这些特性的调节作用。突变分析确定了影响受体特性及其调控的关键剪接残基的作用。此外,变体的冷冻电镜结构显示,GluK1 中外显子 9 的存在并不影响脱敏状态下的受体结构或结构域排列。因此,我们的研究首次提供了 GluK1-1a 受体的详细结构和功能特征,突出了剪接插入物在调节受体特性及其调制过程中的作用。
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来源期刊
eLife
eLife BIOLOGY-
CiteScore
12.90
自引率
3.90%
发文量
3122
审稿时长
17 weeks
期刊介绍: eLife is a distinguished, not-for-profit, peer-reviewed open access scientific journal that specializes in the fields of biomedical and life sciences. eLife is known for its selective publication process, which includes a variety of article types such as: Research Articles: Detailed reports of original research findings. Short Reports: Concise presentations of significant findings that do not warrant a full-length research article. Tools and Resources: Descriptions of new tools, technologies, or resources that facilitate scientific research. Research Advances: Brief reports on significant scientific advancements that have immediate implications for the field. Scientific Correspondence: Short communications that comment on or provide additional information related to published articles. Review Articles: Comprehensive overviews of a specific topic or field within the life sciences.
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