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1.
Journal of Evolutionary Biochemistry and Physiology - Glutamatergic transmission is responsible for most of excitatory synaptic processes in the central nervous system of vertebrates. Glutamatergic... 相似文献
2.
In experiments on hippocampal and striatal neurons, it was demonstrated using specific blockers with different three-dimensional structures that the main difference between channel binding sites in the AMPA and NMDA receptors is the dissimilar location of the nucleophilic region. 相似文献
3.
Neurological glutamate receptors are among the most important and intensely studied protein ligand binding systems in humans. They are crucial for the functioning of the central nervous system and involved in a variety of pathologies. Apart from the neurotransmitter glutamate, several artificial, agonistic and antagonistic ligands are known. Of particular interest here are novel photoswitchable agonists that would open the field of optogenetics to glutamate receptors. The receptor proteins are complex, membrane-bound multidomain oligomers that undergo large scale functional conformational changes, making detailed studies of their atomic structure challenging. Therefore, a thorough understanding of the microscopic details of ligand binding and receptor activation remains elusive in many cases. This topic has been successfully addressed by theoretical studies in the past and in this paper, we present extensive molecular dynamics simulation and free energy calculation results on the binding of AMPA and an AMPA derivative, which is the basis for designing light-sensitive ligands. We provide a two-step model for ligand binding domain activation and predict binding free energies for novel compounds in good agreement to experimental observations. 相似文献
4.
Young-Jun Kim Oghomwen Igiesuorobo Cathy I. Ramos Hong Bao Bing Zhang Mihaela Serpe 《PLoS genetics》2015,11(2)
Stabilization of neurotransmitter receptors at postsynaptic specializations is a key step in the assembly of functional synapses. Drosophila Neto (Neuropillin and Tolloid-like protein) is an essential auxiliary subunit of ionotropic glutamate receptor (iGluR) complexes required for the iGluRs clustering at the neuromuscular junction (NMJ). Here we show that optimal levels of Neto are crucial for stabilization of iGluRs at synaptic sites and proper NMJ development. Genetic manipulations of Neto levels shifted iGluRs distribution to extrajunctional locations. Perturbations in Neto levels also produced small NMJs with reduced synaptic transmission, but only Neto-depleted NMJs showed diminished postsynaptic components. Drosophila Neto contains an inhibitory prodomain that is processed by Furin1-mediated limited proteolysis. neto null mutants rescued with a Neto variant that cannot be processed have severely impaired NMJs and reduced iGluRs synaptic clusters. Unprocessed Neto retains the ability to engage iGluRs in vivo and to form complexes with normal synaptic transmission. However, Neto prodomain must be removed to enable iGluRs synaptic stabilization and proper postsynaptic differentiation. 相似文献
5.
Interference of S-Alkyl Derivatives of Glutathione with Brain Ionotropic Glutamate Receptors 总被引:1,自引:0,他引:1
Zsolt Jenei Réka Janáky Vince Varga Pirjo Saransaari Simo S. Oja 《Neurochemical research》1998,23(8):1085-1091
The effects of glutathione, glutathione sulfonate and S-alkyl derivatives of glutathione on the binding of glutamate and selective ligands of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors were studied with mouse synaptic membranes. The effects of glutathione and its analogues on 45Ca2+ influx were also estimated in cultured rat cerebellar granule cells. Reduced and oxidized glutathione, glutathione sulfonate, S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione inhibited the Na+-independent binding of L-[3H]glutamate. They strongly inhibited also the binding of (S)-2-amino-3-hydroxy-5-[3H]methyl-4-isoxazolepropionate [3H]AMPA (IC50 values: 0.8–15.9 M). S-Alkylation of glutathione rendered the derivatives unable to inhibit [3H]kainate binding. The NMDA-sensitive binding of L-[3H]glutamate and the binding of 3-[(R)-2-carboxypiperazin-4-yl][1,2-3H]propyl-1-phosphonate ([3H]CPP, a competitive antagonist at NMDA sites) were inhibited by the peptides at micromolar concentrations. The strychnine-insensitive binding of the NMDA coagonist [3H]glycine was attenuated only by oxidized glutathione and glutathione sulfonate. All peptides slightly enhanced the use-dependent binding of [3H]dizocilpine (MK-801) to the NMDA-gated ionophores. This effect was additive with the effect of glycine but not with that of saturating concentrations of glutamate or glutamate plus glycine. The glutamate- and NMDA-evoked influx of 45Ca2+ into cerebellar granule cells was inhibited by the S-alkyl derivatives of glutathione. We conclude that besides glutathione the endogenous S-methylglutathione and glutathione sulfonate and the synthetic S-alkyl derivatives of glutathione act as ligands of the AMPA and NMDA receptors. In the NMDA receptor-ionophore these glutathione analogues bind preferably to the glutamate recognition site via their -glutamyl moieties. 相似文献
6.
棕榈酰化是一种可逆的翻译后修饰,其对蛋白质的定位和功能具有重要的调节意义.离子型谷氨酸受体有N-甲基-D-天冬氨酸(NMDA)受体、α-氨基羟甲基恶唑丙酸(AMPA)受体和人海藻酸受体.近期研究发现,它们的棕榈酰化修饰对其膜表面分布和内化均具有重要的意义.其中NMDA受体在其C末端有2个不同的棕榈酰化位点.1个位于C末端近膜区(CysclusterⅠ),它的棕榈酰化可以增高酪氨酸的磷酸化水平,增加受体膜表面分布,影响神经元中NMDA受体的组构性内化;另1个位于C末端中部(CysclusterⅡ),它受到蛋白质酰基转移酶GODZ的调节,使得受体在高尔基体大量积聚,从而影响受体的膜表面分布.与NMDA受体相似,AMPA受体也存在2个棕榈酰化位点.1个位于在第2跨膜域,受蛋白质酰基转移酶GODZ的调节,能导致AMPA受体在高尔基体的积聚.另1个位点在受体C末端近膜区,它的棕榈酰化能降低AMPA受体和4.1N蛋白的相互作用,并调节受体的内化.这两种离子型谷氨酸受体在棕榈酰化机制上虽然存在差异,但均对受体的运输、膜表面分布和内化具有十分重要的作用. 相似文献
7.
Phenotypic plasticity is the ability held in many organisms to produce different phenotypes with a given genome in response to environmental stimuli, such as temperature, nutrition and various biological interactions. It seems likely that environmental signals induce a variety of mechanistic responses that influence ontogenetic processes. Inducible defenses, in which prey animals alter their morphology, behavior and/or other traits to help protect against direct or latent predation threats, are among the most striking examples of phenotypic plasticity. The freshwater microcrustacean Daphnia pulex forms tooth-like defensive structures, “neckteeth,” in response to chemical cues or signals, referred to as “kairomones,” in this case released from phantom midge larvae, a predator of D. pulex. To identify factors involved in the reception and/or transmission of a kairomone, we used microarray analysis to identify genes up-regulated following a short period of exposure to the midge kairomone. In addition to identifying differentially expressed genes of unknown function, we also found significant up-regulation of genes encoding ionotropic glutamate receptors, which are known to be involved in neurotransmission in many animal species. Specific antagonists of these receptors strongly inhibit the formation of neckteeth in D. pulex, although agonists did not induce neckteeth by themselves, indicating that ionotropic glutamate receptors are necessary but not sufficient for early steps of neckteeth formation in D. pulex. Moreover, using co-exposure of D. pulex to antagonists and juvenile hormone (JH), which physiologically mediates neckteeth formation, we found evidence suggesting that the inhibitory effect of antagonists is not due to direct inhibition of JH synthesis/secretion. Our findings not only provide a candidate molecule required for the inducible defense response in D. pulex, but also will contribute to the understanding of complex mechanisms underlying the recognition of environmental changes, which form the basis of phenotypic plasticity. 相似文献
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Kainate receptors (KARs) are a class of ionotropic glutamate receptors that are expressed throughout the central nervous system. The function and subcellular localization of KARs are tightly regulated by accessory proteins. We have previously identified the single-pass transmembrane proteins, Neto1 and Neto2, to be associated with native KARs. In the hippocampus, Neto1, but not Neto2, controls the abundance and modulates the kinetics of postsynaptic KARs. Here we evaluated whether Neto2 regulates synaptic KAR levels in the cerebellum where Neto1 expression is limited to the deep cerebellar nuclei. In the cerebellum, where Neto2 is present abundantly, we found a ∼40% decrease in GluK2-KARs at the postsynaptic density (PSD) of Neto2-null mice. No change, however, was observed in total level of GluK2-KARs, thereby suggesting a critical role of Neto2 on the synaptic localization of cerebellar KARs. The presence of a putative class II PDZ binding motif on Neto2 led us to also investigate whether it interacts with PDZ domain-containing proteins previously implicated in regulating synaptic abundance of KARs. We identified a PDZ-dependent interaction between Neto2 and the scaffolding protein GRIP. Furthermore, coexpression of Neto2 significantly increased the amount of GRIP associated with GluK2, suggesting that Neto2 may promote and/or stabilize GluK2:GRIP interactions. Our results demonstrate that Neto2, like Neto1, is an important auxiliary protein for modulating the synaptic levels of KARs. Moreover, we propose that the interactions of Neto1/2 with various scaffolding proteins is a critical mechanism by which KARs are stabilized at diverse synapses. 相似文献
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Amber Clayton Robert J.C. Gilbert Karl Harlos E. Yvonne Jones 《Journal of molecular biology》2009,392(5):1125-105
Ionotropic glutamate receptors are functionally diverse but have a common architecture, including the 400-residue amino-terminal domain (ATD). We report a 1.8-Å resolution crystal structure of human GluR2-ATD. This dimeric structure provides a mechanism for how the ATDs can drive receptor assembly and subtype-restricted composition. Lattice contacts in a 4.1-Å resolution crystal form reveal a tetrameric (dimer-dimer) arrangement consistent with previous cellular and cryo-electron microscopic data for full-length AMPA receptors. 相似文献
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† Paula Agostinho †Carlos B. Duarte ‡Catarina R. Oliveira 《Journal of neurochemistry》1996,67(3):1153-1163
Abstract: The effect of oxidative stress induced by the oxidant pair ascorbate/Fe2+ on the activity of ionotropic glutamate receptors was studied in cultured chick retina cells. The release of [3H]GABA and the increase of the intracellular free Na+ concentration ([Na+]i), evoked by glutamate receptor agonists, were used as functional assays for the activity of the receptors. The results show that the maximal release of [3H]GABA evoked by kainate (KA; ~20% of the total) or AMPA (~11% of the total) was not different in control and peroxidized cells, whereas the EC50 values determined for peroxidized cells (33.6 ± 1.7 and 8.0 ± 2.0 µM for KA and AMPA, respectively) were significantly lower than those determined under control conditions (54.1 ± 6.6 and 13.0 ± 2.2 µM for KA and AMPA, respectively). The maximal release of [3H]GABA evoked by NMDA under K+ depolarization was significantly higher in peroxidized cells (7.5 ± 0.5% of the total) as compared with control cells (4.0 ± 0.2% of the total), and the effect of oxidative stress was significantly reduced by a phospholipase A2 inhibitor or by fatty acid-free bovine serum albumin. The change in the intracellular [Na+]i evoked by saturating concentrations of NMDA under depolarizing conditions was significantly higher in peroxidized cells (8.9 ± 0.6 mM) than in control cells (5.9 ± 1.0 mM). KA, used at a subsaturating concentration (35 µM), evoked significantly greater increases of the [Na+]i in peroxidized cells (11.8 ± 1.7 mM) than in control cells (7.1 ± 0.8 mM). A saturating concentration (150 µM) of this agonist triggered similar increases of the [Na+]i in control and peroxidized cells. Accordingly, the maximal number of binding sites for (+)-5-[3H]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([3H]MK-801) was increased after peroxidation, whereas the maximal number of binding sites for [3H]KA was not affected by oxidative stress. These data suggest that under oxidative stress the activity of the ionotropic glutamate receptors is increased, with the NMDA receptor being the most affected by peroxidation. 相似文献
11.
Vincent Croset Raphael Rytz Scott F. Cummins Aidan Budd David Brawand Henrik Kaessmann Toby J. Gibson Richard Benton 《PLoS genetics》2010,6(8)
Ionotropic glutamate receptors (iGluRs) are a highly conserved family of ligand-gated ion channels present in animals, plants, and bacteria, which are best characterized for their roles in synaptic communication in vertebrate nervous systems. A variant subfamily of iGluRs, the Ionotropic Receptors (IRs), was recently identified as a new class of olfactory receptors in the fruit fly, Drosophila melanogaster, hinting at a broader function of this ion channel family in detection of environmental, as well as intercellular, chemical signals. Here, we investigate the origin and evolution of IRs by comprehensive evolutionary genomics and in situ expression analysis. In marked contrast to the insect-specific Odorant Receptor family, we show that IRs are expressed in olfactory organs across Protostomia—a major branch of the animal kingdom that encompasses arthropods, nematodes, and molluscs—indicating that they represent an ancestral protostome chemosensory receptor family. Two subfamilies of IRs are distinguished: conserved “antennal IRs,” which likely define the first olfactory receptor family of insects, and species-specific “divergent IRs,” which are expressed in peripheral and internal gustatory neurons, implicating this family in taste and food assessment. Comparative analysis of drosophilid IRs reveals the selective forces that have shaped the repertoires in flies with distinct chemosensory preferences. Examination of IR gene structure and genomic distribution suggests both non-allelic homologous recombination and retroposition contributed to the expansion of this multigene family. Together, these findings lay a foundation for functional analysis of these receptors in both neurobiological and evolutionary studies. Furthermore, this work identifies novel targets for manipulating chemosensory-driven behaviours of agricultural pests and disease vectors. 相似文献
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《Journal of molecular biology》2023,435(6):167970
Ionotropic glutamate receptors are ligand-gated cation channels that play essential roles in the excitatory synaptic transmission throughout the central nervous system. A number of open-pore structures of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid (AMPA)-type glutamate receptors became available recently by cryo-electron microscopy (cryo-EM). These structures provide valuable insights into the conformation of the selectivity filter (SF), the part of the ion channel that determines the ion selectivity. Nonetheless, due to the moderate resolution of the cryo-EM structures, detailed information such as ion occupancy of monovalent and divalent cations as well as positioning of the side-chains in the SF is still missing. Here, in an attempt to obtain high-resolution information about glutamate receptor SFs, we incorporated partial SF sequences of the AMPA and kainate receptors into the bacterial tetrameric cation channel NaK, which served as a structural scaffold. We determined a series of X-ray structures of NaK-CDI, NaK-SDI and NaK-SELM mutants at 1.42–2.10 Å resolution, showing distinct ion occupation of different monovalent cations. Molecular dynamics (MD) simulations of NaK-CDI indicated the channel to be conductive to monovalent cations, which agrees well with our electrophysiology recordings. Moreover, previously unobserved structural asymmetry of the SF was revealed by the X-ray structures and MD simulations, implying its importance in ion non-selectivity of tetrameric cation channels. 相似文献
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Elisa Carpanese Paola Moretto Viviana Filpa Silvia Marchet Elisabetta Moro Francesca Crema Gianmario Frigo Cristina Giaroni 《PloS one》2014,9(11)
Alterations of the enteric glutamatergic transmission may underlay changes in the function of myenteric neurons following intestinal ischemia and reperfusion (I/R) contributing to impairment of gastrointestinal motility occurring in these pathological conditions. The aim of the present study was to evaluate whether glutamate receptors of the NMDA and AMPA/kainate type are involved in myenteric neuron cell damage induced by I/R. Primary cultured rat myenteric ganglia were exposed to sodium azide and glucose deprivation (in vitro chemical ischemia). After 6 days of culture, immunoreactivity for NMDA, AMPA and kainate receptors subunits, GluN1 and GluA1–4, GluK1–3 respectively, was found in myenteric neurons. In myenteric cultured ganglia, in normal metabolic conditions, -AP5, an NMDA antagonist, decreased myenteric neuron number and viability, determined by calcein AM/ethidium homodimer-1 assay, and increased reactive oxygen species (ROS) levels, measured with hydroxyphenyl fluorescein. CNQX, an AMPA/kainate antagonist exerted an opposite action on the same parameters. The total number and viability of myenteric neurons significantly decreased after I/R. In these conditions, the number of neurons staining for GluN1 and GluA1–4 subunits remained unchanged, while, the number of GluK1–3-immunopositive neurons increased. After I/R, -AP5 and CNQX, concentration-dependently increased myenteric neuron number and significantly increased the number of living neurons. Both -AP5 and CNQX (100–500 µM) decreased I/R-induced increase of ROS levels in myenteric ganglia. On the whole, the present data provide evidence that, under normal metabolic conditions, the enteric glutamatergic system exerts a dualistic effect on cultured myenteric ganglia, either by improving or reducing neuron survival via NMDA or AMPA/kainate receptor activation, respectively. However, blockade of both receptor pathways may exert a protective role on myenteric neurons following and I/R damage. The neuroprotective effect may depend, at least in part, on the ability of both receptors to increase intraneuronal ROS production. 相似文献
14.
Zielińska M Hilgier W Borkowska HD Oja SS Saransaari P Goryński P Albrecht J 《Neurochemical research》2002,27(1-2):37-42
Accumulation of taurine (Tau), glutamate (Glu) and glutamine (Gln) was measured in vivo in microdialysates of the rat striatum following a direct application to the microdialysis tube of 60 mM ammonium chloride which renders the final ammonia concentration in the extracellular space to 5 mM. The following compounds were coadministered with ammonia to distinguish between the different mechanisms that may underlie the accumulation of amino acids: ion transport inhibitors, diisothiocyanostilbene-2,28-disulfonate (DIDS) and furosemide, a Glu transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC), an NMDA receptor antagonist dizocilpine (MK-801) and an 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate (KA) receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX). Ammonia stimulated Tau accumulation in the microdialysates to 250% of the basal value. Furosemide did not significantly affect the stimulation by ammonia and DIDS only moderately depressed the effect. The ammonia-dependent Tau accumulation was increased by 50% in the presence of PDC and reduced by 35% in the presence dizocilpine and DNQX. In the microdialysates ammonia stimulated Glu and Gln accumulation somewhat less than Tau accumulation. Except for stimulation of Gln accumulation by DNQX, the effects were not modified by any of the cotreatments. The results are consistent with the assumption that ammonia stimulates Tau efflux mainly via activation of ionotropic Glu receptors. 相似文献
15.
Interference of S-Nitrosoglutathione with the Binding of Ligands to Ionotropic Glutamate Receptors in Pig Cerebral Cortical Synaptic Membranes 总被引:2,自引:0,他引:2
Hermann A Varga V Janáky R Dohovics R Saransaari P Oja SS 《Neurochemical research》2000,25(8):1119-1124
The interactions of S-nitrosoglutathione (GSNO) with the ionotropic glutamate receptors were studied on synaptic membranes isolated from the pig cerebral cortex. GSNO displaced the binding of [3H]glutamate, 3-[(R)-2-carboxypiperazin-4-yl][3H]propyl-1-phosphonate ([3H]CPP), a competitive N-methyl-D-aspartate (NMDA) antagonist, and [3H]kainate, with IC50 values in the low micromolar range. It failed to displace (S)-5-fluoro-[3H]willardiine, a selective agonist of 2-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. Reduced and oxidized glutathione were almost as effective as GSNO in glutamate and CPP binding. Of the three, GSNO was the most potent in kainate binding. They all stimulated [3H]dizocilpine binding in a concentration-dependent manner. This effect was additive to that of glycine and not mimicked by NO donors such as S-nitroso-N-acetylpenicillamine, 5-amino-3-morpholinyl-1,2,3-oxadiazolium chloride (SIN-1) and nitroglycerin. We assume that GSNO may act as an endogenous ligand at the NMDA and non-NMDA classes of glutamate receptors. In this manner it may facilitate NO transfer and target its delivery to specific sites in these receptors. 相似文献
16.
exocyst复合物在分泌过程中起重要作用.可是分子机理尚未研究透彻.通过TMP/UV的基因敲除方法,得到了exocyst复合物中一种组分sec-10的缺陷型线虫.药学结果显示这种线虫神经信号传递存在缺陷,可是电生理的方法证明在神经肌肉接头处的已报道离子型受体和野生型相比并未发生改变.因此猜测,sec-10并未直接影响神经肌肉接头处的离子型受体,而是通过其他途径来行使功能. 相似文献
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《Structure (London, England : 1993)》2020,28(10):1168-1178.e2
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20.
exocyst复合物在分泌过程中起重要作用.可是分子机理尚未研究透彻.通过TMP/UV的基因敲除方法,得到了exocyst复合物中一种组分sec-10的缺陷犁线虫.药学结果显示这种线虫神经信号传递存在缺陷,可是电生理的方法证明在神经肌肉接头处的已报道离子型受体和野生型相比并未发生改变.因此猜测,sec-10并未直接影响神经肌肉接头处的离子型受体,而是通过其他途径来行使功能. 相似文献