Synaptic role of the AMPA receptor N-terminal domain

AMPA 受体 N 末端结构域的突触作用

• 批准号: BB/N002113/1
• 负责人: Ingo Greger
• 金额: $ 34.76万
• 依托单位: MRC Laboratory of Molecular Biology
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FN002113%2F1
• 关键词: Synaptic; role; AMPA; receptor; terminal

The brain is made up of nerve cells or neurons (~90 billions in the human brain, ~ 75 million in the mouse), which communicate via specific cell junctions termed synapses. Synapses are the sites where information between neurons is transmitted and stored (i.e. laid down as memories); information storage at synapses is believed to require plastic changes in synapse function and efficacy. Signaling across synapses is initiated by the release of neurotransmitter chemicals from an 'upstream' neuron, forming the pre-synaptic site, onto the post-synapse of a downstream recipient cell. A primary neurotransmitter in the mammalian brain is the amino acid glutamate, which, when released by the pre-synapse, activates recipient protein molecules on the post-synapse. These neurotransmitter recipients are termed receptors and lie at the heart of this proposal. The glutamate receptor central to the application is the AMPA-receptor (AMPA-R; based on its selective pharmacological properties). AMPA-Rs initiate excitatory neurotransmission, i.e. they depolarize the post-synaptic membrane in response to binding glutamate. Depolarization results from a glutamate-triggered flux of positively charged particles (cations), through a narrow opening in the AMPA-R channel, into the post-synaptic neuron. Synaptic potentiation, the substrate for information storage, results from the recruitment of additional AMPA-Rs to the post-synapse - this recruitment gives rise to increased net cation-influx and augments the level of depolarization. Potentiated transmission also requires the clustering of AMPA-Rs at the synapse and their retention opposite glutamate-release sites. In this proposal we will investigate mechanisms underlying AMPA-R clustering and retention at synapses in response to potentiating stimuli. We have preliminary evidence suggesting that the distal portion of the AMPA-R, the N-terminal domain (or NTD) regulates receptor diffusion/retention and clustering at post-synaptic sites. Hence, the NTD appears to play a currently elusive role in AMPA-R-mediated synapse potentiation and therefore in synaptic learning. AMPA-R retention also stabilizes post-synaptic structures, and our data point to a role for the NTD in this process. Since synapse elimination is a hallmark of neurodegneration, NTD-mediated receptor retention would have the potential to oppose neurological disorders such as Alzheimer's disease and related dementias. These observations, together with our accumulating evidence for the NTD as novel drug target, highlight a key role for the AMPA-R NTD in synapse function. In summary, our proposed work will provide mechanistic information into the role of AMPARs in synaptic learning and synapse stabilization.

大脑由神经细胞或神经元组成（人脑中约 900 亿个，小鼠大脑中约 7500 万个），它们通过称为突触的特定细胞连接进行通信。突触是神经元之间传输和存储信息（即形成记忆）的场所；突触的信息存储被认为需要突触功能和功效的可塑性改变。跨突触的信号传导是通过从形成突触前位点的“上游”神经元释放神经递质化学物质到下游受体细胞的突触后来启动的。哺乳动物大脑中的主要神经递质是氨基酸谷氨酸，当突触前​​释放时，它会激活突触后的受体蛋白分子。这些神经递质接受者被称为受体，是该提议的核心。该应用的核心谷氨酸受体是 AMPA 受体（AMPA-R；基于其选择性药理学特性）。 AMPA-R 启动兴奋性神经传递，即它们响应结合谷氨酸而使突触后膜去极化。去极化是由谷氨酸触发的带正电粒子（阳离子）通量通过 AMPA-R 通道中的狭窄开口进入突触后神经元造成的。突触增强是信息存储的底物，是由于将额外的 AMPA-R 募集到突触后而产生的 - 这种募集会增加净阳离子流入并增强去极化水平。增强的传递还需要 AMPA-R 在突触处聚集，并保留在谷氨酸释放位点对面。在本提案中，我们将研究 AMPA-R 聚集和突触保留以响应增强刺激的潜在机制。我们有初步证据表明 AMPA-R 的远端部分、N 末端结构域（或 NTD）调节突触后位点的受体扩散/保留和聚集。因此，NTD 似乎在 AMPA-R 介导的突触增强以及突触学习中发挥着目前难以捉摸的作用。 AMPA-R 保留还可以稳定突触后结构，我们的数据表明 NTD 在此过程中发挥作用。由于突触消除是神经变性的一个标志，NTD 介导的受体保留将有可能对抗阿尔茨海默病和相关痴呆等神经系统疾病。这些观察结果与我们积累的 NTD 作为新药物靶点的证据一起，强调了 AMPA-R NTD 在突触功能中的关键作用。总之，我们提出的工作将为 AMPAR 在突触学习和突触稳定中的作用提供机制信息。

项目成果

Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.

• DOI: 10.1016/j.str.2018.10.017
• 发表时间: 2019-02
• 期刊: Structure
• 影响因子: 5.7
• 作者: J. Lee;James M. Krieger;B. Herguedas;J. García-Nafría;Anindita Dutta;S. Shaikh;I. Greger;I. Bahar-I.

Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions.

• DOI: 10.1016/j.neulet.2018.02.050
• 发表时间: 2019-05-01
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Krieger J;Lee JY;Greger IH;Bahar I
• 通讯作者: Bahar I

Druggability Simulations and X-ray Crystallography Reveal a Ligand-binding Site in the GluA3 AMPA Receptor N-terminal Domain

成药性模拟和 X 射线晶体学揭示了 GluA3 AMPA 受体 N 末端结构域中的配体结合位点

• DOI: 10.2139/ssrn.3188417
• 发表时间: 2018
• 期刊: SSRN Electronic Journal
• 作者: Lee J

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels.

• DOI: 10.1124/pharmrev.120.000131
• 发表时间: 2021-10
• 期刊: Pharmacological reviews
• 影响因子: 21.1
• 作者: Hansen KB;Wollmuth LP;Bowie D;Furukawa H;Menniti FS;Sobolevsky AI;Swanson GT;Swanger SA;Greger IH;Nakagawa T;McBain CJ;Jayaraman V;Low CM;Dell'Acqua ML;Diamond JS;Camp CR;Perszyk RE;Yuan H;Traynelis SF
• 通讯作者: Traynelis SF