AMPA 受体氨基末端结构域在突触定位中的亚基特异性作用。
Subunit-specific role for the amino-terminal domain of AMPA receptors in synaptic targeting.
机构信息
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143;
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143.
出版信息
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7136-7141. doi: 10.1073/pnas.1707472114. Epub 2017 Jun 19.
Abstract
The amino-terminal domain (ATD) of AMPA receptors (AMPARs) accounts for approximately 50% of the protein, yet its functional role, if any, remains a mystery. We have discovered that the translocation of surface GluA1, but not GluA2, AMPAR subunits to the synapse requires the ATD. GluA1A2 heteromers in which the ATD of GluA1 is absent fail to translocate, establishing a critical role of the ATD of GluA1. Inserting GFP into the ATD interferes with the constitutive synaptic trafficking of GluA1, but not GluA2, mimicking the deletion of the ATD. Remarkably, long-term potentiation (LTP) can override the masking effect of the GFP tag. GluA1, but not GluA2, lacking the ATD fails to show LTP. These findings uncover a role for the ATD in subunit-specific synaptic trafficking of AMPARs, both constitutively and during plasticity. How LTP, induced postsynaptically, engages these extracellular trafficking motifs and what specific cleft proteins participate in the process remain to be elucidated.
摘要
AMPA 受体（AMPAR）的氨基末端结构域（ATD）约占蛋白质的 50%，但其功能作用（如果有的话）仍然是个谜。我们发现，表面 GluA1 而不是 GluA2 AMPAR 亚基向突触的易位需要 ATD。缺少 GluA1 的 ATD 的 GluA1A2 异源二聚体不能易位，这确立了 GluA1 的 ATD 的关键作用。将 GFP 插入 ATD 会干扰 GluA1 的组成型突触运输，但不会干扰 GluA2，模拟 ATD 的缺失。值得注意的是，长时程增强（LTP）可以覆盖 GFP 标签的掩蔽效应。缺乏 ATD 的 GluA1 但不是 GluA2 无法显示 LTP。这些发现揭示了 ATD 在 AMPAR 的亚基特异性突触运输中的作用，无论是在组成型还是在可塑性期间。LTP 如何在后突触诱导这些细胞外运输基序，以及哪些特定的裂孔蛋白参与该过程，仍有待阐明。
相似文献
1
Subunit-specific role for the amino-terminal domain of AMPA receptors in synaptic targeting.AMPA 受体氨基末端结构域在突触定位中的亚基特异性作用。
Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7136-7141. doi: 10.1073/pnas.1707472114. Epub 2017 Jun 19.
2
The AMPA Receptor Subunit GluA1 is Required for CA1 Hippocampal Long-Term Potentiation but is not Essential for Synaptic Transmission.AMPA 受体亚基 GluA1 对于 CA1 海马长时程增强是必需的，但对于突触传递不是必需的。
Neurochem Res. 2019 Mar;44(3):549-561. doi: 10.1007/s11064-017-2425-3. Epub 2017 Nov 3.
3
The amino-terminal domain of GluA1 mediates LTP maintenance via interaction with neuroplastin-65.谷氨酸受体 1 的氨基末端结构域通过与神经可塑性蛋白 65 相互作用来介导长时程增强的维持。
Proc Natl Acad Sci U S A. 2021 Mar 2;118(9). doi: 10.1073/pnas.2019194118.
4
Calcineurin regulates synaptic Ca-permeable AMPA receptors in hypothalamic presympathetic neurons via α2δ-1-mediated GluA1/GluA2 assembly.钙调神经磷酸酶通过 α2δ-1 介导的 GluA1/GluA2 组装调节下丘脑节前交感神经元中的突触钙通透性 AMPA 受体。
J Physiol. 2024 May;602(10):2179-2197. doi: 10.1113/JP286081. Epub 2024 Apr 17.
5
Input- and subunit-specific AMPA receptor trafficking underlying long-term potentiation at hippocampal CA3 synapses.海马体CA3突触处长期增强作用背后的输入及亚基特异性AMPA受体转运。
Eur J Neurosci. 2004 Jul;20(1):101-10. doi: 10.1111/j.1460-9568.2004.03461.x.
6
Selective regulation of GluA subunit synthesis and AMPA receptor-mediated synaptic function and plasticity by the translation repressor 4E-BP2 in hippocampal pyramidal cells.翻译：翻译抑制因子 4E-BP2 对海马锥体神经元中 GluA 亚基合成和 AMPA 受体介导的突触功能和可塑性的选择性调节。
J Neurosci. 2013 Jan 30;33(5):1872-86. doi: 10.1523/JNEUROSCI.3264-12.2013.
7
Phosphorylation of 4.1N by CaMKII Regulates the Trafficking of GluA1-containing AMPA Receptors During Long-term Potentiation in Acute Rat Hippocampal Brain Slices.CaMKII对4.1N的磷酸化作用在急性大鼠海马脑片长时程增强过程中调节含GluA1的AMPA受体的转运
Neuroscience. 2024 Jan 9;536:131-142. doi: 10.1016/j.neuroscience.2023.11.016. Epub 2023 Nov 21.
8
Induction and expression of GluA1 (GluR-A)-independent LTP in the hippocampus.海马体中不依赖于谷氨酸受体A1（GluR-A）的长时程增强（LTP）的诱导与表达
Eur J Neurosci. 2009 Mar;29(6):1141-52. doi: 10.1111/j.1460-9568.2009.06677.x.
9
Glutamate receptor subunit GluA1 is necessary for long-term potentiation and synapse unsilencing, but not long-term depression in mouse hippocampus.谷氨酸受体亚基 GluA1 对于小鼠海马体的长时程增强和突触去抑制是必需的，但对于长时程抑制则不是必需的。
Brain Res. 2012 Jan 30;1435:8-14. doi: 10.1016/j.brainres.2011.11.029. Epub 2011 Nov 19.
10
Persistent synaptic scaling independent of AMPA receptor subunit composition.持续的突触缩放与 AMPA 受体亚基组成无关。
J Neurosci. 2013 Jul 17;33(29):11763-7. doi: 10.1523/JNEUROSCI.1102-13.2013.
引用本文的文献
1
Dynamic extracellular interactions with AMPA receptors.与AMPA受体的动态细胞外相互作用。
bioRxiv. 2025 Jul 14:2025.07.11.664166. doi: 10.1101/2025.07.11.664166.
2
LARGE protein drives activity-induced homeostatic resetting.大型蛋白质驱动活动诱导的稳态重置。
Sci Adv. 2025 Aug;11(31):eadt0703. doi: 10.1126/sciadv.adt0703. Epub 2025 Jul 30.
3
Architecture, dynamics and biogenesis of GluA3 AMPA glutamate receptors.GluA3 AMPA 型谷氨酸受体的结构、动力学及生物发生
Nature. 2025 Jul 1. doi: 10.1038/s41586-025-09325-z.
4
Gating and noelin clustering of native Ca-permeable AMPA receptors.天然钙通透性AMPA受体的门控和Noelin聚集
Nature. 2025 Jun 23. doi: 10.1038/s41586-025-09289-0.
5
AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders.AMPA受体扩散捕获机制作为神经退行性疾病和神经精神疾病的早期治疗靶点。
Transl Neurodegener. 2025 Feb 11;14(1):8. doi: 10.1186/s40035-025-00470-z.
6
The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty.谷氨酸受体1（GluA1）的胞质尾调节细胞内α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体的转运以及向齿状回γ-氨基丁酸（GABA）能中间神经元的突触传递，控制对新奇事物的反应。
bioRxiv. 2024 Dec 1:2024.12.01.626277. doi: 10.1101/2024.12.01.626277.
7
The VGCC auxiliary subunit α2δ1 is an extracellular GluA1 interactor and regulates LTP, spatial memory, and seizure susceptibility.电压门控钙通道辅助亚基α2δ1是一种细胞外谷氨酸受体1相互作用分子，可调节长时程增强、空间记忆和癫痫易感性。
bioRxiv. 2024 Dec 2:2024.12.02.626379. doi: 10.1101/2024.12.02.626379.
8
Genetically encoded intrabody probes for labeling and manipulating AMPA-type glutamate receptors.基因编码的内体探针用于标记和操纵 AMPA 型谷氨酸受体。
Nat Commun. 2024 Nov 29;15(1):10374. doi: 10.1038/s41467-024-54530-5.
9
Proton-triggered rearrangement of the AMPA receptor N-terminal domains impacts receptor kinetics and synaptic localization.质子触发的 AMPA 受体 N 端结构域重排影响受体动力学和突触定位。
Nat Struct Mol Biol. 2024 Oct;31(10):1601-1613. doi: 10.1038/s41594-024-01369-5. Epub 2024 Aug 13.
10
Nanoscale organization is changed in native, surface AMPARs by mouse brain region and tauopathy.在天然的、位于表面的α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体（AMPARs）中，纳米级组织会因小鼠脑区和tau蛋白病而发生改变。
bioRxiv. 2024 Jul 23:2024.07.22.604547. doi: 10.1101/2024.07.22.604547.
本文引用的文献
1
Synaptic transmission and plasticity require AMPA receptor anchoring via its N-terminal domain.突触传递和可塑性需要通过AMPA受体的N端结构域进行锚定。
Elife. 2017 Mar 14;6:e23024. doi: 10.7554/eLife.23024.
2
A Brief History of Long-Term Potentiation.长时程增强现象的简史。
Neuron. 2017 Jan 18;93(2):281-290. doi: 10.1016/j.neuron.2016.12.015.
3
Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking.海人酸受体的氨基末端结构域决定了其在转运过程中对Neto辅助亚基的不同依赖性。
Proc Natl Acad Sci U S A. 2017 Jan 31;114(5):1159-1164. doi: 10.1073/pnas.1619253114. Epub 2017 Jan 18.
4
Presynaptic Neuronal Pentraxin Receptor Organizes Excitatory and Inhibitory Synapses.突触前神经元五聚体受体组织兴奋性和抑制性突触。
J Neurosci. 2017 Feb 1;37(5):1062-1080. doi: 10.1523/JNEUROSCI.2768-16.2016. Epub 2016 Dec 16.
5
Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor.不同的亚基结构域决定了海人酸受体的突触稳定性和特异性。
Cell Rep. 2016 Jul 12;16(2):531-544. doi: 10.1016/j.celrep.2016.05.093. Epub 2016 Jun 23.
6
Transsynaptic Modulation of Kainate Receptor Functions by C1q-like Proteins.C1q 样蛋白对红藻氨酸受体功能的突触前调制。
Neuron. 2016 May 18;90(4):752-67. doi: 10.1016/j.neuron.2016.04.001. Epub 2016 Apr 28.
7
Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons.五聚素协调小白蛋白中间神经元的兴奋性突触成熟和回路整合。
Neuron. 2015 Mar 18;85(6):1257-72. doi: 10.1016/j.neuron.2015.02.020. Epub 2015 Mar 5.
8
Mapping the interaction sites between AMPA receptors and TARPs reveals a role for the receptor N-terminal domain in channel gating.绘制AMPA受体与跨膜AMPAR调节蛋白之间的相互作用位点揭示了受体N端结构域在通道门控中的作用。
Cell Rep. 2014 Oct 23;9(2):728-40. doi: 10.1016/j.celrep.2014.09.029. Epub 2014 Oct 16.
9
The N-terminal domain modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor desensitization.N 端结构域调节 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体脱敏。
J Biol Chem. 2014 May 9;289(19):13197-205. doi: 10.1074/jbc.M113.526301. Epub 2014 Mar 20.
10
GluA1 trafficking and metabotropic NMDA: addressing results from other laboratories inconsistent with ours.GluA1 转运和代谢型 NMDA：解决与我们不一致的其他实验室的结果。
Philos Trans R Soc Lond B Biol Sci. 2013 Dec 2;369(1633):20130145. doi: 10.1098/rstb.2013.0145. Print 2014 Jan 5.
Zotero 插件