Glutamate receptors: brain function and signal transduction
Glutamate receptors: brain function and signal transduction
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DOI：
10.1016/s0165-0173(97)00033-7
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发表时间：
1998-05-01
影响因子：
--
通讯作者：
Okada, M
中科院分区：
文献类型：
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作者：
Nakanishi, S;Nakajima, Y;Okada, M
谷氨酸受体在神经可塑性、神经发育和神经变性中起重要作用。N-甲基-D-天冬氨酸（NMDA）受体和α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）/红藻氨酸受体作为谷氨酸门控阳离子通道，而代谢型受体（mGluRs）通过G蛋白调节第二信使的产生。本实验室和其他实验室的分子研究表明，NMDA受体和mGluRs以多亚基（NMDAR 1和NMDAR 2A-2D）和多亚型（mGluR 1-mGluR 8）的形式存在。鉴于谷氨酸受体的分子多样性，我们探讨了谷氨酸受体不同成员的功能和细胞内信号转导机制。在视觉系统中，视网膜双极细胞接收来自光感受器的谷氨酸传输，并有助于将视觉信号分离为ON和OFF通路。分子克隆的mGluR 6在视杆和视锥系统中的ON-双极细胞的突触后位点被限制性地表达。mGluR 6的基因靶向导致ON响应的丧失而不改变OFF响应，并且严重损害检测视觉对比度。由于AMPA受体介导OFF双极细胞中的OFF反应，两种不同类型的谷氨酸受体有效地作用于ON和OFF反应。mGluR 1和mGluR 5均以相同的激动剂选择性与肌醇三磷酸（IP 3）/钙信号转导偶联。单细胞胞内钙（[Ca 2 +]（i））记录表明，谷氨酸分别在mGluR 1表达细胞和mGluR 5表达细胞中引起非振荡和振荡[Ca 2 +]（i）反应。这种差异是由一个单一的氨基酸取代，mGluR 1的天冬氨酸或mGluR 5的苏氨酸，在G蛋白相互作用的羧基末端结构域。mGluR 5的苏氨酸的蛋白激酶G磷酸化负责诱导mGluR 5表达细胞和培养的神经胶质细胞中的[Ca 2 +]（i）振荡。因此，这两种密切相关的mGluR亚型介导了谷氨酸传递中的不同细胞内信号传导。(C)1998 Elsevier Science B. V.保留所有权利。
Glutamate receptors are important in neural plasticity, neural development and neurodegeneration. N-methyl-D-aspartate (NMDA) receptors and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors act as glutamate-gated cation channels, whereas metabotropic receptors (mGluRs) modulate the production of second messengers via G proteins. Molecular studies from our and other laboratories indicated that NMDA receptors and mGluRs exist as multiple subunits (NMDAR1 and NMDAR2A-2D) and multiple subtypes (mGluR1-mGluR8). In light of the molecular diversity of glutamate receptors, we explored the function and intracellular signaling mechanisms of different members of glutamate receptors. In the visual system, retinal bipolar cells receive glutamate transmission from photoreceptors and contribute to segregating visual signals into ON and OFF pathways. The molecularly cloned mGluR6 is restrictedly expressed at the postsynaptic site of ON-bipolar cells in both rod and cone systems. Gene targeting of mGluR6 results in a loss of ON responses without changing OFF responses and severely impairs detecting visual contrasts. Since AMPA receptors mediate OFF responses in OFF-bipolar cells, two distinct types of glutamate receptors effectively operate for ON and OFF responses. mGluR1 and mGluR5 are both coupled to inositol triphosphate (IP3)/calcium signal transduction with an identical agonist selectivity. Single-cell intracellular calcium ([Ca2+](i)) recordings indicated that glutamate evokes a non-oscillatory and oscillatory [Ca2+](i) response in mGluR1-expressing and mGluR5-expressing cells, respectively. This difference results from a single amino acid substitution, aspartate of mGluR1 or threonine of mGluR5, at the G protein-interacting carboxy-terminal domains. Protein kinase G phosphorylation of the threonine of mGluR5 is responsible for inducing [Ca2+](i) oscillations in mGluR5-expressing cells and cultured glial cells. Thus, the two closely related mGluR subtypes mediate diverging intracellular signaling in glutamate transmission. (C) 1998 Elsevier Science B.V. All rights reserved.