NMDA受体与Ⅰ组代谢型谷氨酸受体的相互作用

谷氨酸是哺乳动物中枢神经系统重要兴奋性神经递质,参与学习、记忆、药物依赖成瘾及神经系统退行性疾病等多种病理生理过程。谷氨酸通过激活离子型（iGluRs）和代谢型谷氨酸受体（mGluRs）发挥作用。业已有研究提示iGluRs和mGluRs之间存在相互作用,但具体机制尚待阐明。本文从蛋白分子结构、突触可塑性、相互作用可能涉及的信号分子和通路等方面综述了NMDAR与Ⅰ组mGluRs之间的相互作用,旨在为深入研究谷氨酸受体之间的相互作用提供线索。     

GABA受体与药物依赖性的研究进展

药物成瘾是一种全球性的公共卫生问题,其发生机制十分复杂。γ-氨基丁酸(γ-aminobutyric acid,GABA)是中枢神经系统中主要的抑制性神经递质,其通过调节GABA受体(如:GABA_A,GABA_B)的活性参与多种药物成瘾和依赖性的发生与发展过程。吗啡、可卡因、甲基苯丙胺等药物引起的奖赏、戒断和复吸作用与GABA受体的激活或抑制密切相关。本文将对GABA受体在药物依赖中的作用及机制进行综述,从而为治疗药物成瘾提供新的策略。     

下丘脑食欲素在药物成瘾中的作用

下丘脑是调控自然奖赏的重要脑区,它能特异性地表达一种神经肽——食欲素(orexin),这种神经肽在药物奖赏中的作用受到广泛关注。在成瘾研究中,发现不同脑区中的食欲素神经元对奖赏和动机行为的调节作用是不相同的:围穹窿区(PFA)和背内侧下丘脑区(DMH)的食欲素神经元主要参与激活应激系统,而外侧下丘脑(LH)的食欲素神经元主要通过激活与奖赏学习相关的大脑环路参与奖赏行为的调控。提示食欲素系统可在延长戒断防止复吸发生中成为新的研究目标,食欲素受体可以作为治疗药物成瘾的一种新的治疗靶标。     

《自然-神经科学》：谷氨酸神经传递素受体或有助抑制戒断复发

对可卡因成瘾戒断的大鼠来说,增强其脑中一定谷氨酸神经传递素受体的功能可抑制其觅药行为,这是《自然-神经科学》上的一项报告得出的结论。这项发现意味着科学家可开发出一种潜在的预防药瘾复发的药物治疗方法。     

靶向神经小胶质细胞的戒毒治疗策略

鸦片用于镇痛治疗有千余年历史, 其滥用导致药物成瘾, 带来严重的社会和医学问题。关于鸦片等精神活性物质的研究主要围绕 神经元,当前的戒毒药物作用于神经元的阿片受体或离子通道受体,然而其戒毒效果非常有限。神经元不是中枢神经系统中调节神经信号 转导的唯一组分,神经小胶质细胞占中枢神经系统的 10%~15%,然而其作用和功能在很长一段时间被忽视。鸦片、可卡因、冰毒及其他 精神活性物质激活 Toll 样受体 4 (TLR4),活化小胶质细胞,产生大量炎症因子,从而调节奖赏信号通路,增加神经元的兴奋性,导致药物 依赖和成瘾,因而 TLR4 是开发新型戒毒药物的靶点。综述药物成瘾的小胶质细胞分子机制以及靶向小胶质细胞的治疗药物成瘾的药物发现。     

突触前代谢型谷氨酸受体调节神经递质的释放

谷氨酸通过激活离子型受体（iGluR)介导快速兴奋性突触传递,参与脑内几乎所有生理过程。谷氨酸过量释放可导致与脑缺血,缺氧及变性疾病有关的兴奋毒作用,最终引起神经元的死亡。代谢型谷氨酸受体（mGluRs)是一个与G－蛋白偶联的受体家族,分三型共八个亚型。其中Ⅱ和Ⅲ型mGluRs主要位于突触前,发挥对谷氨酸释放的负反馈调节。Ⅲ型mGluRs中的mGluR7位于谷氨酸能末梢突触前膜的活性区,发挥自身受体的作用,对正常情况下突触传递过程的谷氨酸释放进行负反馈调节;而属于Ⅱ型的mGluR2及属于Ⅲ型的mGluR4和mGluR8,则位于远离突有膜活性区的外突触区,因而正常突触传递过程中释放的谷氨酸量不能激活它们。只有在突触传递增强的情况下才被激活,抑制递质的释放。国外,mGluRs还分布在GABA能纤维末梢,通过突触前机制抑制GABA的释放。对突触前膜受体尤其是位于外突触区的mGluRs受体的研究,将有可能开发出理想的工具药,从而预防和阻止谷氨酸过量释放引起的神经毒及神经元的死亡。     

食欲素信号系统在成瘾中的作用

成瘾是对成瘾物质的强迫性、持续性需求并缺乏控制能力的行为,它会导致大脑中枢奖赏回路的改变。下丘脑是调控自然奖赏的重要脑区,它能特异性地表达一种被称为食欲素(orexins/hypocretins)的神经肽。食欲素通过作用于食欲素受体调控睡眠、觉醒状态,同时,食欲素受体在药物成瘾和奖赏相关的行为中也有重要作用,投射到不同脑区的食欲素对不同药物导致的成瘾调节作用也不同,调控食欲素信号系统,将可能成为治疗成瘾的重要方法。本文重点总结了食欲素信号系统在不同药物成瘾过程中的作用的最新研究进展。     

CAL与mGluR1相互作用抑制mGluR1过度激活诱导的细胞毒性作用

代谢型谷氨酸受体1(mGluR1)过度激活介导的谷氨酸兴奋性毒性是帕金森病(PD)的主要发病机制之一。在临床试验中应用mGluRs的负性变构调节剂缓解PD病人的运动障碍已有报道,但由于精确调控mGluRs表达或活性的局限性,目前,在PD的治疗中仍存在一些问题。因此,寻找能够精确调控mGluR1表达及活性的小分子药物或内源性基因,将有可能成为解决目前PD治疗中存在问题的有效方法。本文通过体内和体外实验,对囊性纤维跨膜调节器相关配体(CAL)在mGluR1过度激活诱导的细胞毒性中的作用和机制进行研究。研究结果显示,在工具细胞HEK293中,应用mGluR1的激动剂激活受体,CAL与mGluR1的相互作用明显增强(P< 0.05),且CAL通过与mGluR1相互作用,抑制mGluR1过度激活诱导的细胞凋亡及其下游信号通路的激活。在鱼藤酮诱导的PD大鼠模型中,过表达CAL通过抑制mGluR1下游通路的激活,减少鱼藤酮引起的神经损伤(P< 0.001)。本文揭示了一种调控mGluR1活性的新机制,希望为神经系统疾病的治疗和相关研究提供新思路。     

谷氨酸下调培养海马神经元AMPA 受体GluR2亚单位的表达

目的研究在癫痫发病过程中,谷氨酸对AMPA受体Glu R2亚单位表达变化的影响。方法用RT-PCR和Western Blot方法观察谷氨酸诱导培养大鼠海马神经元AMPA受体Glu R2亚单位mRNA和蛋白的表达变化。结果在谷氨酸刺激后2h,8h,12h,培养海马神经元Glu R2mRNA和蛋白表达明显下降,与对照组相比,差异有显著性(P<0.05),而非NMDA受体拮抗剂CNQX能阻断此变化。结论在癫痫等疾病中,谷氨酸能通过激活AMAP/KA受体下调AMPA受体GluR2亚单位的表达,参与发病过程。     

阿片成瘾机制研究进展及治疗展望

关于阿片类药物成瘾机制的研究是药物成瘾研究中的一个热点,本文从参与阿片成瘾的神经递质系统及其相互作用、不同阿片受体在成瘾过程中的作用、学习记忆与阿片成瘾的关系、成瘾性药物的细胞内信号转导机制等几个方面介绍了近年来的研究进展,并对阿片类药物成瘾治疗和预防和新方法进行了展望。     

Glutamate and Brain Glutaminases in Drug Addiction

Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.     

Glutamatergic mechanisms in different disease states: overview and therapeutical implications -- an introduction

Summary.  Glutamate is the most widely distributed excitatory transmitter in the central nervous system (CNS). It is acting via large – and still growing – families of receptors: NMDA-, AMPA-, kainate-, and metabotropic receptors. Glutamate has been implicated in a large number of CNS disorders, and it is hoped that novel glutamate receptor ligands offer new therapeutic possibilites in disease states such as chronic pain, stroke, epilepsy, depression, drug addiction and dependence or Parkinson's disease. While an extensive preclinical literature exists showing potential beneficial effects of NMDA-, AMPA-, kainate- and metabotropic receptor ligands, only NMDA receptor antagonists have been characterized clinically to any appreciable degree. In these trials it has been shown that while several compounds are therapeutically active, they also produce serious side effects at therapeutic doses. Current interest largely centers on the development of receptor subtype-selective compounds, namely compounds selective for receptors containing the NR2B subunit. Preclinical findings and the first clinical results are encouraging, and it may be that such subunit-selective compounds may have a sufficiently wide therapeutic window to be safe for human use. Received July 6, 2001 Accepted August 6, 2001 Published online August 9, 2002     

Long-term potentiation of neuronal glutamate transporters

Persistent, use-dependent modulation of synaptic strength has been demonstrated for fast synaptic transmission mediated by glutamate and has been hypothesized to underlie persistent behavioral changes ranging from memory to addiction. Glutamate released at synapses is sequestered by the action of excitatory amino acid transporters (EAATs) in glia and postsynaptic neurons. So, the efficacy of glutamate transporter function is crucial for regulating glutamate spillover to adjacent presynaptic and postsynaptic receptors and the consequent induction of plastic or excitotoxic processes. Here, we report that tetanic stimulation of cerebellar climbing fiber-Purkinje cell synapses results in long-term potentiation (LTP) of a climbing fiber-evoked glutamate transporter current recorded in Purkinje cells. This LTP is postsynaptically expressed and requires activation of an mGluR1/PKC cascade. Together with a simultaneously induced long-term depression (LTD) of postsynaptic AMPA receptors, this might reflect an integrated antiexcitotoxic cellular response to strong climbing fiber synaptic activation, as occurs following an ischemic episode.     

Effect of intracerebral administration of NMDA and AMPA on dopamine and glutamate release in the ventral pallidum and on motor behavior

The present study investigates the modulation of the ventral tegmental area (VTA)-ventral pallidum (VP) dopaminergic system by glutamate agonists in rats. The glutamate receptor agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) were infused via reversed microdialysis into the VTA, and dopamine (DA), glutamate, and aspartate levels in the VTA and ipsilateral VP were monitored together with motor behavior screened in an open field. NMDA (750 microM) infusion, as well as AMPA (50 microM) infusion, induced an increase of DA and glutamate levels in the VTA, followed by an increase of DA levels in the ipsilateral VP and by enhanced locomotor activity. The increase of DA in the VP was similar after administration of these two glutamate agonists, although motor activity was more pronounced and showed an earlier onset after NMDA infusion. Glutamate levels in the VP were not increased by the stimulation of DA release. It is concluded that DA is released from mesencephalic DA neurons projecting to the VP and that these neurons are controlled by glutamatergic systems, via NMDA and AMPA receptors. Thus, DA in the VP has to be considered as a substantial modulator. Dysregulation of the mesopallidal DA neurons, as well as their glutamatergic control, may play an additional or distinct role in disorders like schizophrenia and drug addiction.     

谷氨酸受体分子的多样性及其分子机理

谷氨酸是中枢神经系统一种重要的兴奋性神经递质,它与相应受体分子相互作用,通过细胞膜对阳离子通透性的改变或与G蛋白和第二信使系统相偶联,从而引起一系列复杂的信号转导反应。近年有关谷氨酸受体分子及其基因的研究表明:由于多基因家族、选择性剪接、RNA编辑以及异聚体形成等分子机理,使谷氨酸受体分子的结构和功能具有多样性,这种多样性是生物多样性的分子基础,也在微观水平上证明了生物多样性的原理。这方面的深入探索必将为中枢神经系统该受体表达及调控以及相关神经精神疾病发病的分子机理和治疗性药物设计提供新的线索。     

Molecular mechanisms underlying specificity of excitotoxic signaling in neurons

The central role of glutamate receptors in mediating excitotoxic neuronal death in stroke, epilepsy and trauma has been well established. Glutamate is the major excitatory amino acid transmitter within the CNS and it's signaling is mediated by a number of postsynaptic ionotropic and metabotropic receptors. Although calcium ions are considered key regulators of excitotoxicity, new evidence suggests that specific second messenger pathways rather than total Ca(2+) load, are responsible for mediating neuronal degeneration. Glutamate receptors are found localized at the synapse within electron dense structures known as the postsynaptic density (PSD). Localization at the PSD is mediated by binding of glutamate receptors to submembrane proteins such as actin and PDZ containing proteins. PDZ domains are conserved motifs that mediate protein-protein interactions and self-association. In addition to glutamate receptors PDZ-containing proteins bind a multitude of intracellular signal molecules including nitric oxide synthase. In this way PDZ proteins provide a mechanism for clustering glutamate receptors at the synapse together with their corresponding signal transduction proteins. PSD organization may thus facilitate the individual neurotoxic signal mechanisms downstream of receptors during glutamate overactivity. Evidence exists showing that inhibiting signals downstream of glutamate receptors, such as nitric oxide and PARP-1 can reduce excitotoxic insult. Furthermore we have shown that uncoupling the interaction between specific glutamate receptors from their PDZ proteins protects neurons against glutamate-mediated excitotoxicity. These findings have significant implications for the treatment of neurodegenerative diseases using therapeutics that specifically target intracellular protein-protein interactions.     

Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking

Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy.     

谷氨酸信号通路及其在骨力学信号转导通路中潜在的功能

自在中枢神经系统中发现谷氨酸发挥功能以来,谷氨酸受体及其在突触内膜偶联的信号通路,就成为神经系统研究的重要内容。近年的研究显示,谷氨酸受体及其胞内信号通路在包括骨在内的非神经组织中表达和发挥功能,在骨细胞中有表达谷氨酸受体、转运子的证据,因而有假说认为谷氨酸成了骨中力学信号潜在的转导子,但还缺乏有利的证据支持。简要综述了谷氨酸信号通路及其在骨中的功能,并就其在骨力学信号转导中潜在的功能和作用机制进行了探讨。     

The Structure of (?)-Kaitocephalin Bound to the Ligand Binding Domain of the (S)-α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)/Glutamate Receptor,GluA2

Glutamate receptors mediate the majority of excitatory synaptic transmission in the central nervous system, and excessive stimulation of these receptors is involved in a variety of neurological disorders and neuronal damage from stroke. The development of new subtype-specific antagonists would be of considerable therapeutic interest. Natural products can provide important new lead compounds for drug discovery. The only natural product known to inhibit glutamate receptors competitively is (−)-kaitocephalin, which was isolated from the fungus Eupenicillium shearii and found to protect CNS neurons from excitotoxicity. Previous work has shown that it is a potent antagonist of some subtypes of glutamate receptors (AMPA and NMDA, but not kainate). The structure of kaitocephalin bound to the ligand binding domain of the AMPA receptor subtype, GluA2, is reported here. The structure suggests how kaitocephalin can be used as a scaffold to develop more selective and high affinity antagonists for glutamate receptors.