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Kampstra, Arieke Suzanna Berendina, Jacqueline Stephanie Dekkers, Mikhail Volkov, Annemarie L. Dorjée, Lise Hafkenscheid, Ayla C. Kempers, Myrthe van Delft, et al. "Different classes of anti-modified protein antibodies are induced on exposure to antigens expressing only one type of modification." Annals of the Rheumatic Diseases 78, no. 7 (May 31, 2019): 908–16. http://dx.doi.org/10.1136/annrheumdis-2018-214950.
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ObjectivesAutoantibodies against post-translationally modified proteins (anti-modified protein antibodies or AMPAs) are a hallmark of rheumatoid arthritis (RA). A variety of classes of AMPAs against different modifications on proteins, such as citrullination, carbamylation and acetylation, have now been described in RA. At present, there is no conceptual framework explaining the concurrent presence or mutual relationship of different AMPA responses in RA. Here, we aimed to gain understanding of the co-occurrence of AMPA by postulating that the AMPA response shares a common ‘background’ that can evolve into different classes of AMPAs.MethodsMice were immunised with modified antigens and analysed for AMPA responses. In addition, reactivity of AMPA purified from patients with RA towards differently modified antigens was determined.ResultsImmunisation with carbamylated proteins induced AMPAs recognising carbamylated proteins and also acetylated proteins. Similarly, acetylated proteins generated (autoreactive) AMPAs against other modifications as well. Analysis of anti-citrullinated protein antibodies from patients with RA revealed that these also display reactivity to acetylated and carbamylated antigens. Similarly, anti-carbamylated protein antibodies showed cross-reactivity against all three post-translational modifications.ConclusionsDifferent AMPA responses can emerge from exposure to only a single type of modified protein. These findings indicate that different AMPA responses can originate from a common B-cell response that diversifies into multiple distinct AMPA responses and explain the presence of multiple AMPAs in RA, one of the hallmarks of the disease.
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Gainey, Melanie A., Vedakumar Tatavarty, Marc Nahmani, Heather Lin, and Gina G. Turrigiano. "Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade." Proceedings of the National Academy of Sciences 112, no. 27 (June 24, 2015): E3590—E3599. http://dx.doi.org/10.1073/pnas.1510754112.
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Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.
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Kalappa, Bopanna I., Charles T. Anderson, Jacob M. Goldberg, Stephen J. Lippard, and Thanos Tzounopoulos. "AMPA receptor inhibition by synaptically released zinc." Proceedings of the National Academy of Sciences 112, no. 51 (December 8, 2015): 15749–54. http://dx.doi.org/10.1073/pnas.1512296112.
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The vast amount of fast excitatory neurotransmission in the mammalian central nervous system is mediated by AMPA-subtype glutamate receptors (AMPARs). As a result, AMPAR-mediated synaptic transmission is implicated in nearly all aspects of brain development, function, and plasticity. Despite the central role of AMPARs in neurobiology, the fine-tuning of synaptic AMPA responses by endogenous modulators remains poorly understood. Here we provide evidence that endogenous zinc, released by single presynaptic action potentials, inhibits synaptic AMPA currents in the dorsal cochlear nucleus (DCN) and hippocampus. Exposure to loud sound reduces presynaptic zinc levels in the DCN and abolishes zinc inhibition, implicating zinc in experience-dependent AMPAR synaptic plasticity. Our results establish zinc as an activity-dependent, endogenous modulator of AMPARs that tunes fast excitatory neurotransmission and plasticity in glutamatergic synapses.
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Mao, Xia, Xinglong Gu, and Wei Lu. "GSG1L regulates the strength of AMPA receptor-mediated synaptic transmission but not AMPA receptor kinetics in hippocampal dentate granule neurons." Journal of Neurophysiology 117, no. 1 (January 1, 2017): 28–35. http://dx.doi.org/10.1152/jn.00307.2016.
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GSG1L is an AMPA receptor (AMPAR) auxiliary subunit that regulates AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its physiological roles in other types of neurons remain to be characterized. Here, we investigated the role of GSG1L in hippocampal dentate granule cells and found that GSG1L is important for the regulation of synaptic strength but is not critical for the modulation of AMPAR deactivation and desensitization kinetics. These data demonstrate a neuronal type-specific role of GSG1L and suggest that physiological function of AMPAR auxiliary subunits may vary in different types of neurons. NEW & NOTEWORTHY GSG1L is a newly identified AMPA receptor (AMPAR) auxiliary subunit and plays a unique role in the regulation of AMPAR trafficking and function in hippocampal CA1 pyramidal neurons. However, its role in the regulation of AMPARs in hippocampal dentate granule cells remains to be characterized. The current work reveals that GSG1L regulates strength of AMPAR-mediated synaptic transmission but not the receptor kinetic properties in hippocampal dentate granule neurons.
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Hanley, J. G. "Molecular mechanisms for regulation of AMPAR trafficking by PICK1." Biochemical Society Transactions 34, no. 5 (October 1, 2006): 931–35. http://dx.doi.org/10.1042/bst0340931.
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AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor trafficking is a fundamental mechanism for regulating synaptic strength, and hence may underlie cellular processes involved in learning and memory. PICK1 (protein that interacts with protein C-kinase) has recently emerged as a key regulator of AMPAR (AMPA receptor) traffic, and the precise molecular mechanisms of PICK1's action are just beginning to be unravelled. In this review, I summarize recent findings that describe some important molecular characteristics of PICK1 with respect to AMPAR cell biology.
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Morrell, Craig N., Henry Sun, Masahiro Ikeda, Jean-Claude Beique, Anne Marie Swaim, Emily Mason, Tanika V. Martin, et al. "Glutamate mediates platelet activation through the AMPA receptor." Journal of Experimental Medicine 205, no. 3 (February 18, 2008): 575–84. http://dx.doi.org/10.1084/jem.20071474.
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Glutamate is an excitatory neurotransmitter that binds to the kainate receptor, the N-methyl-D-aspartate (NMDA) receptor, and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR). Each receptor was first characterized and cloned in the central nervous system (CNS). Glutamate is also present in the periphery, and glutamate receptors have been identified in nonneuronal tissues, including bone, heart, kidney, pancreas, and platelets. Platelets play a central role in normal thrombosis and hemostasis, as well as contributing greatly to diseases such as stroke and myocardial infarction. Despite the presence of glutamate in platelet granules, the role of glutamate during hemostasis is unknown. We now show that activated platelets release glutamate, that platelets express AMPAR subunits, and that glutamate increases agonist-induced platelet activation. Furthermore, we demonstrate that glutamate binding to the AMPAR increases intracellular sodium concentration and depolarizes platelets, which are important steps in platelet activation. In contrast, platelets treated with the AMPAR antagonist CNQX or platelets derived from GluR1 knockout mice are resistant to AMPA effects. Importantly, mice lacking GluR1 have a prolonged time to thrombosis in vivo. Our data identify glutamate as a regulator of platelet activation, and suggest that the AMPA receptor is a novel antithrombotic target.
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Wei, Mengping, Jian Zhang, Moye Jia, Chaojuan Yang, Yunlong Pan, Shuaiqi Li, Yiwen Luo, et al. "α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors." Proceedings of the National Academy of Sciences 113, no. 19 (April 25, 2016): E2695—E2704. http://dx.doi.org/10.1073/pnas.1524589113.
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In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.
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Barkóczi, Balázs, Gábor Juhász, Robert G. Averkin, Imre Vörös, Petra Vertes, Botond Penke, and Viktor Szegedi. "GluA1 Phosphorylation Alters Evoked Firing PatternIn Vivo." Neural Plasticity 2012 (2012): 1–8. http://dx.doi.org/10.1155/2012/286215.
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AMPA and NMDA receptors convey fast synaptic transmission in the CNS. Their relative contribution to synaptic output and phosphorylation state regulate synaptic plasticity. The AMPA receptor subunit GluA1 is central in synaptic plasticity. Phosphorylation of GluA1 regulates channel properties and trafficking. The firing rate averaged over several hundred ms is used to monitor cellular input. However, plasticity requires the timing of spiking within a few ms; therefore, it is important to understand how phosphorylation governs these events. Here, we investigate whether the GluA1 phosphorylation (p-GluA1) alters the spiking patterns of CA1 cellsin vivo. The antidepressant Tianeptine was used for inducing p-GluA1, which resulted in enhanced AMPA-evoked spiking. By comparing the spiking patterns of AMPA-evoked activity with matched firing rates, we show that the spike-trains after Tianeptine application show characteristic features, distinguishing from spike-trains triggered by strong AMPA stimulation. The interspike-interval distributions are different between the two groups, suggesting that neuronal output may differ when new inputs are activated compared to increasing the gain of previously activated receptors. Furthermore, we also show that NMDA evokes spiking with different patterns to AMPA spike-trains. These results support the role of the modulation of NMDAR/AMPAR ratio and p-GluA1 in plasticity and temporal coding.
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Myme, Chaelon I. O., Ken Sugino, Gina G. Turrigiano, and Sacha B. Nelson. "The NMDA-to-AMPA Ratio at Synapses Onto Layer 2/3 Pyramidal Neurons Is Conserved Across Prefrontal and Visual Cortices." Journal of Neurophysiology 90, no. 2 (August 2003): 771–79. http://dx.doi.org/10.1152/jn.00070.2003.
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To better understand regulation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complements across the cortex, and to investigate NMDA receptor (NMDAR)-based models of persistent activity, we compared NMDA/AMPA ratios in prefrontal (PFC) and visual cortex (VC) in rat. Whole cell voltage-clamp responses were recorded in brain slices from layer 2/3 pyramidal cells of the medial PFC and VC of rats aged p16–p21. Mixed miniature excitatory postsynaptic currents (mEPSCs) having AMPA receptor (AMPAR)- and NMDAR-mediated components were isolated in nominally 0 Mg2+ ACSF. Averaged mEPSCs were well-fit by double exponentials. No significant differences in the NMDA/AMPA ratio (PFC: 27 ± 1%; VC: 28 ± 3%), peak mEPSC amplitude (PFC: 19.1 ± 1 pA; VC: 17.5 ± 0.7 pA), NMDAR decay kinetics (PFC: 69 ± 8 ms; VC: 67 ± 6 ms), or degree of correlation between NMDAR- and AMPAR-mediated mEPSC components were found between the areas (PFC: n = 27; VC: n = 28). Recordings from older rats (p26–29) also showed no differences. EPSCs were evoked extracellularly in 2 mM Mg2+ at depolarized potentials; although the average NMDA/AMPA ratio was larger than that observed for mEPSCs, the ratio was similar in the two regions. In nominally 0 Mg2+ and in the presence of CNQX, spontaneous activation of NMDAR increased recording noise and produced a small tonic depolarization which was similar in both areas. We conclude that this basic property of excitatory transmission is conserved across PFC and VC synapses and is therefore unlikely to contribute to differences in firing patterns observed in vivo in the two regions.
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Rawal, Bijal, and Klaus Ballanyi. "Mediation of Sinusoidal Network Oscillations in the Locus Coeruleus of Newborn Rat Slices by Pharmacologically Distinct AMPA and KA Receptors." Brain Sciences 12, no. 7 (July 19, 2022): 945. http://dx.doi.org/10.3390/brainsci12070945.
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Brain control by locus coeruleus (LC) neurons involves afferent glutamate (Glu) inputs. In newborns, LC Glu receptors and responses may be sparse due to immaturity of the brain circuits providing such input. However, we reported, using newborn rat brain slices, that Glu and its ionotropic receptor (iGluR) agonist NMDA transform spontaneous local field potential (LFP) rhythm. Here, we studied whether α-amino-3-hydroxy-5-methyl-4-isoxazole propionic-acid (AMPA) and kainate (KA) iGluR subtypes also transform the LFP pattern. AMPA (0.25–0.5 µM) and KA (0.5–2.5 µM) merged ~0.2 s-lasting bell-shaped LFP events occurring at ~1 Hz into ~40% shorter and ~4-fold faster spindle-shaped and more regular sinusoidal oscillations. The AMPA/KA effects were associated with a 3.1/4.3-fold accelerated phase-locked single neuron spiking due to 4.0/4.2 mV depolarization while spike jitter decreased to 64/42% of the control, respectively. Raising extracellular K+ from 3 to 9 mM increased the LFP rate 1.4-fold or elicited slower multipeak events. A blockade of Cl−-mediated inhibition with gabazine (5 μM) plus strychnine (10 μM) affected neither the control rhythm nor AMPA/KA oscillations. GYKI-53655 (25 μM) blocked AMPA (but not KA) oscillations whereas UBP-302 (25 μM) blocked KA (but not AMPA) oscillations. Our findings revealed that AMPA and KA evoke a similar novel neural network discharge pattern transformation type by acting on pharmacologically distinct AMPAR and KA receptors. This shows that already the neonatal LC can generate oscillatory network behaviors that may be important, for example, for responses to opioids.
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Mitchell-Flack, Marisa, Ying Zheng, Hana Goldschmidt, Kacey Rajkovich, Makenzie Higgins, Bian Liu, Richard Huganir, Hong Yu, and Drew Pardoll. "The role of ionotropic AMPA receptors in T cell tolerance." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 54.03. http://dx.doi.org/10.4049/jimmunol.208.supp.54.03.
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Abstract The ability of T cells to mount effective immune responses to pathogens and cancer while remaining tolerant to self-tissue is critical for maintaining immune homeostasis. Previously, our group identified neuritin, a neuronal protein, as a highly differentially expressed gene in anergic and regulatory T cells. Furthermore, our results indicate neuritin deficient mice exhibit enhanced autoimmunity due, in part, to dysfunctional regulatory T cells. Neuritin was recently identified as an accessory component of the ionotropic AMPA receptor (AMPAR) complex in neurons. AMPAR complexes are typically found on the post-synaptic neuronal cell and mediate glutamate dependent cation flux. Given our previous findings involving neuritin in autoimmunity and this newly identified interaction between neuritin and AMPAR, we sought to evaluate whether there is a role for the AMPAR in T cell tolerance. Here, we show that the AMPAR is expressed in CD4+ T cells and that the specific deletion of the AMPAR in T cells (AMPAR KO) leads to significantly reduced disease pathogenesis in an experimental autoimmune encephalomyelitis (EAE) model. The spinal cord inflammatory immune infiltrates from AMPAR KO mice are markedly reduced in cell number, proliferative state, and expression of proinflammatory cytokines compared to wild type (WT) mice. In addition, we have observed an increase in the CD4+FoxP3+ regulatory cell population among spinal cord infiltrates from AMPAR KO EAE mice. Consistent with the EAE model, AMPAR KO T cells also exhibit increased induced regulatory T cell development during in vitro differentiation. Taken together our results support a previously unappreciated role for ionotropic AMPA receptors in regulating T cell tolerance.
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Chen, Zhiqiang, Marcello Peppi, Sharon G. Kujawa, and William F. Sewell. "Regulated Expression of Surface AMPA Receptors Reduces Excitotoxicity in Auditory Neurons." Journal of Neurophysiology 102, no. 2 (August 2009): 1152–59. http://dx.doi.org/10.1152/jn.00288.2009.
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Dynamic regulation of the expression of surface AMPA receptors (AMPARs) is a key mechanism to modulate synaptic strength and efficacy in the CNS and also to regulate auditory sensitivity. Here we address the role of surface AMPAR expression in excitotoxicity by blocking clathrin-mediated AMPAR endocytosis in auditory neurons. We used a membrane-permeable, dynamin-derived, myristoylated peptide (myr-Dyn) to inhibit surface AMPAR endocytosis induced by glutamate receptor agonists in culture and by noise exposure in vivo. Myr-Dyn infused into the mouse cochlea induced excitotoxic responses to acoustic stimuli that were normally not excitotoxic. These included vacuolization in the nerve terminals and spiral ganglion as well as irreversible auditory brain stem response threshold shifts. In cultured spiral ganglion neuronal cells, blockade of the reduction of surface AMPARs exacerbated neuronal death by incubation with N-methyl-d-aspartate and AMPA. This excitotoxic neuronal death could be prevented by calpeptin, a calpain-specific inhibitor. These results suggest that the reduction of surface AMPAR by endocytosis during excitatory stimulation plays an important role in limiting the excitotoxic damage to the neuron.
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Giesen, Jan, Ernst-Martin Füchtbauer, Annette Füchtbauer, Klaus Funke, Doris Koesling, and Michael Russwurm. "AMPA Induces NO-Dependent cGMP Signals in Hippocampal and Cortical Neurons via L-Type Voltage-Gated Calcium Channels." Cerebral Cortex 30, no. 4 (November 11, 2019): 2128–43. http://dx.doi.org/10.1093/cercor/bhz227.
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Abstract The nitric oxide (NO)/cGMP signaling cascade has an established role in synaptic plasticity. However, with conventional methods, the underlying cGMP signals were barely detectable. Here, we set out to confirm the well-known NMDA-induced cGMP increases, to test the impact of AMPA on those signals, and to identify the relevant phosphodiesterases (PDEs) using a more sensitive fluorescence resonance energy transfer (FRET)-based method. Therefore, a “knock-in” mouse was generated that expresses a FRET-based cGMP indicator (cGi-500) allowing detection of cGMP concentrations between 100 nM and 3 μM. Measurements were performed in cultured hippocampal and cortical neurons as well as acute hippocampal slices. In hippocampal and cortical neurons, NMDA elicited cGMP signals half as high as the ones elicited by exogenous NO. Interestingly, AMPA increased cGMP independently of NMDA receptors and dependent on NO synthase (NOS) activation. NMDA- and AMPA-induced cGMP signals were not additive indicating that both pathways converge on the level of NOS. Accordingly, the same PDEs, PDE1 and PDE2, were responsible for degradation of NMDA- as well as AMPA-induced cGMP signals. Mechanistically, AMPAR induced calcium influx through L-type voltage-gated calcium channels leading to NOS and finally NO-sensitive guanylyl cyclase activation. Our results demonstrate that in addition to NMDA also AMPA triggers endogenous NO formation and hence cGMP production.
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Sibold, Harry. "AMPA." Air Medical Journal 22, no. 6 (November 2003): 10–11. http://dx.doi.org/10.1016/j.amj.2003.10.012.
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Robinson, Kenneth. "AMPA." Air Medical Journal 23, no. 6 (November 2004): 17–18. http://dx.doi.org/10.1016/j.amj.2004.10.005.
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Robinson, Kenneth. "AMPA." Air Medical Journal 24, no. 1 (January 2005): 13–14. http://dx.doi.org/10.1016/j.amj.2004.11.003.
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Robinson, Kenneth J. "AMPA." Air Medical Journal 24, no. 2 (March 2005): 60–61. http://dx.doi.org/10.1016/j.amj.2005.01.003.
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Robinson, Kenneth J. "AMPA." Air Medical Journal 24, no. 3 (May 2005): 102. http://dx.doi.org/10.1016/j.amj.2005.03.004.
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Robinson, Ken. "AMPA." Air Medical Journal 24, no. 5 (September 2005): 186. http://dx.doi.org/10.1016/j.amj.2005.07.037.
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Twomey, Edward C., Maria V. Yelshanskaya, Robert A. Grassucci, Joachim Frank, and Alexander I. Sobolevsky. "Elucidation of AMPA receptor–stargazin complexes by cryo–electron microscopy." Science 353, no. 6294 (June 30, 2016): 83–86. http://dx.doi.org/10.1126/science.aaf8411.
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AMPA-subtype ionotropic glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and contribute to high cognitive processes such as learning and memory. In the brain, AMPAR trafficking, gating, and pharmacology is tightly controlled by transmembrane AMPAR regulatory proteins (TARPs). Here, we used cryo–electron microscopy to elucidate the structural basis of AMPAR regulation by one of these auxiliary proteins, TARP γ2, or stargazin (STZ). Our structures illuminate the variable interaction stoichiometry of the AMPAR-TARP complex, with one or two TARP molecules binding one tetrameric AMPAR. Analysis of the AMPAR-STZ binding interfaces suggests that electrostatic interactions between the extracellular domains of AMPAR and STZ play an important role in modulating AMPAR function through contact surfaces that are conserved across AMPARs and TARPs. We propose a model explaining how TARPs stabilize the activated state of AMPARs and how the interactions between AMPARs and their auxiliary proteins control fast excitatory synaptic transmission.
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Yang, Zhiyong, Michael Krause, Geeta Rao, Bruce L. McNaughton, and C. A. Barnes. "Synaptic Commitment: Developmentally Regulated Reciprocal Changes in Hippocampal Granule Cell NMDA and AMPA Receptors Over the Lifespan." Journal of Neurophysiology 99, no. 6 (June 2008): 2760–68. http://dx.doi.org/10.1152/jn.01276.2007.
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Synaptic transmission in hippocampal field CA1 is largely N-methyl-d-aspartate receptor (NMDAR) dependent during the early postnatal period. It becomes increasingly mediated by α-amino-3-hydroxy-5-methylisoxazole-4-proprionate (AMPA) receptors until an adult ratio of AMPA to NMDA receptors is achieved. It is shown here that increases in the AMPA receptor (AMPAR)-mediated field potential response continue over the life span of the F-344 rat at the perforant path–granule cell synapse in the dentate gyrus. In contrast, the NMDAR-dependent component of the response decreases with age between 1 and 27 mo, leading to an increase of AMPAR/NMDAR ratio with age. One possible explanation of this age difference is that the AMPAR/NMDAR ratio can be modified by experience. To test the idea that the changed ratio is caused by the old rats' longer lives, an intensive 10-mo period of enrichment treatment was given to a group of animals, beginning at 3 mo of age. Compared with animals housed in standard cages, the enrichment treatment did not alter the glutamatergic response ratio measured with field potential recording methods. These data provide support for the conclusion that the observed change with age is developmentally regulated rather than experience dependent. Given the role of the NMDAR in synaptic plasticity, these changes suggest a progressive commitment of perforant path synapses to particular weights over the life span. One possible implication of this effect includes preservation of selected memories, ultimately at the expense of a reduced capacity to store new information.
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Miles, Carl J., Louis R. Wallace, and H. Anson Moye. "Determination of Glyphosate Herbicide and (Aminomethyl)phosphonic Acid in Natural Waters by Liquid Chromatography Using Pre-Column Fluorogenic Labeling with 9-Fluorenylmethyl Chloroformate." Journal of AOAC INTERNATIONAL 69, no. 3 (May 1, 1986): 458–61. http://dx.doi.org/10.1093/jaoac/69.3.458.
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Abstract An analytical method has been developed for determination of glyphosate herbicide and its major metabolite, (aminomethyl)phosphonic acid (AMFA), in natural waters. Sample pretreatment consisted of filtration, addition of phosphate buffer, concentration by rotary evaporation, and a final filtration before derivatization with 9-fluorenylmethyl chloroformate. The derivatives were separated by anion exchange liquid chromatography and measured with a fluorescence detector. Standard curves were linear over 3 orders of magnitude and minimal detectable quantities were 10 ng/mL for glyphosate and 5 ng/mL for AMPA. The 20-fold concentration factor realized in sample preparation corresponds to ppb method detection limits for glyphosate and AMPA in natural waters. Recovery and storage studies were performed and are discussed.
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Diering, Graham H., Seok Heo, Natasha K. Hussain, Bian Liu, and Richard L. Huganir. "Extensive phosphorylation of AMPA receptors in neurons." Proceedings of the National Academy of Sciences 113, no. 33 (August 1, 2016): E4920—E4927. http://dx.doi.org/10.1073/pnas.1610631113.
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Regulation of AMPA receptor (AMPAR) function is a fundamental mechanism controlling synaptic strength during long-term potentiation/depression and homeostatic scaling. AMPAR function and membrane trafficking is controlled by protein–protein interactions, as well as by posttranslational modifications. Phosphorylation of the GluA1 AMPAR subunit at S845 and S831 play especially important roles during synaptic plasticity. Recent controversy has emerged regarding the extent to which GluA1 phosphorylation may contribute to synaptic plasticity. Here we used a variety of methods to measure the population of phosphorylated GluA1-containing AMPARs in cultured primary neurons and mouse forebrain. Phosphorylated GluA1 represents large fractions from 12% to 50% of the total population under basal and stimulated conditions in vitro and in vivo. Furthermore, a large fraction of synapses are positive for phospho-GluA1–containing AMPARs. Our results support the large body of research indicating a prominent role of GluA1 phosphorylation in synaptic plasticity.
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Kim, Ji-Eun, Duk-Shin Lee, Hana Park, Tae-Hyun Kim, and Tae-Cheon Kang. "AMPA Receptor Antagonists Facilitate NEDD4-2-Mediated GRIA1 Ubiquitination by Regulating PP2B-ERK1/2-SGK1 Pathway in Chronic Epilepsy Rats." Biomedicines 9, no. 8 (August 23, 2021): 1069. http://dx.doi.org/10.3390/biomedicines9081069.
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The neural precursor cell expressed by developmentally downregulated gene 4-2 (NEDD4-2) is a ubiquitin E3 ligase that has a high affinity toward binding and ubiquitinating glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type subunit 1 (GRIA1, also referred to GluR1 or GluA1). Since dysregulation of GRIA1 surface expression is relevant to the responsiveness to AMPA receptor (AMPAR) antagonists (perampanel and GYKI 52466) in chronic epilepsy rats, it is likely that NEDD4-2 may be involved in the pathogenesis of intractable epilepsy. However, the role of NEDD4-2-mediated GRIA1 ubiquitination in refractory seizures to AMPAR antagonists is still unknown. In the present study, both AMPAR antagonists recovered the impaired GRIA1 ubiquitination by regulating protein phosphatase 2B (PP2B)-extracellular signal-regulated kinase 1/2 (ERK1/2)-serum and glucocorticoid-regulated kinase 1 (SGK1)-NEDD4-2 signaling pathway in responders (whose seizure activities are responsive to AMPAR), but not non-responders (whose seizure activities were uncontrolled by AMPAR antagonists). In addition, cyclosporin A (CsA, a PP2B inhibitor) co-treatment improved the effects of AMPAR antagonists in non-responders, independent of AKT signaling pathway. Therefore, our findings suggest that dysregulation of PP2B-ERK1/2-SGK1-NEDD4-2-mediated GRIA1 ubiquitination may be responsible for refractory seizures and that this pathway may be a potential therapeutic target for improving the treatment of intractable epilepsy in response to AMPAR antagonists.
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Nakagawa, Terunaga. "Structures of the AMPA receptor in complex with its auxiliary subunit cornichon." Science 366, no. 6470 (December 5, 2019): 1259–63. http://dx.doi.org/10.1126/science.aay2783.
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In the brain, AMPA-type glutamate receptors (AMPARs) form complexes with their auxiliary subunits and mediate the majority of fast excitatory neurotransmission. Signals transduced by these complexes are critical for synaptic plasticity, learning, and memory. The two major categories of AMPAR auxiliary subunits are transmembrane AMPAR regulatory proteins (TARPs) and cornichon homologs (CNIHs); these subunits share little homology and play distinct roles in controlling ion channel gating and trafficking of AMPAR. Here, I report high-resolution cryo–electron microscopy structures of AMPAR in complex with CNIH3. Contrary to its predicted membrane topology, CNIH3 lacks an extracellular domain and instead contains four membrane-spanning helices. The protein-protein interaction interface that dictates channel modulation and the lipids surrounding the complex are revealed. These structures provide insights into the molecular mechanism for ion channel modulation and assembly of AMPAR/CNIH3 complexes.
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van der Spek, Sophie J. F., Nikhil J. Pandya, Frank Koopmans, Iryna Paliukhovich, Roel C. van der Schors, Mylene Otten, August B. Smit, and Ka Wan Li. "Expression and Interaction Proteomics of GluA1- and GluA3-Subunit-Containing AMPARs Reveal Distinct Protein Composition." Cells 11, no. 22 (November 17, 2022): 3648. http://dx.doi.org/10.3390/cells11223648.
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The AMPA glutamate receptor (AMPAR) is the major type of synaptic excitatory ionotropic receptor in the brain. AMPARs have four different subunits, GluA1–4 (each encoded by different genes, Gria1, Gria2, Gria3 and Gria4), that can form distinct tetrameric assemblies. The most abundant AMPAR subtypes in the hippocampus are GluA1/2 and GluA2/3 heterotetramers. Each subtype contributes differentially to mechanisms of synaptic plasticity, which may be in part caused by how these receptors are regulated by specific associated proteins. A broad range of AMPAR interacting proteins have been identified, including the well-studied transmembrane AMPA receptor regulatory proteins TARP-γ2 (also known as Stargazin) and TARP-γ8, Cornichon homolog 2 (CNIH-2) and many others. Several interactors were shown to affect biogenesis, AMPAR trafficking, and channel properties, alone or in distinct assemblies, and several revealed preferred binding to specific AMPAR subunits. To date, a systematic specific interactome analysis of the major GluA1/2 and GluA2/3 AMPAR subtypes separately is lacking. To reveal interactors belonging to specific AMPAR subcomplexes, we performed both expression and interaction proteomics on hippocampi of wildtype and Gria1- or Gria3 knock-out mice. Whereas GluA1/2 receptors co-purified TARP-γ8, synapse differentiation-induced protein 4 (SynDIG4, also known as Prrt1) and CNIH-2 with highest abundances, GluA2/3 receptors revealed strongest co-purification of CNIH-2, TARP-γ2, and Noelin1 (or Olfactomedin-1). Further analysis revealed that TARP-γ8-SynDIG4 interact directly and co-assemble into an AMPAR subcomplex especially at synaptic sites. Together, these data provide a framework for further functional analysis into AMPAR subtype specific pathways in health and disease.
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Abrahamsson, Therése, Bengt Gustafsson, and Eric Hanse. "AMPA Silencing Is a Prerequisite for Developmental Long-Term Potentiation in the Hippocampal CA1 Region." Journal of Neurophysiology 100, no. 5 (November 2008): 2605–14. http://dx.doi.org/10.1152/jn.90476.2008.
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AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) unsilencing is an often proposed expression mechanism both for developmental long-term potentiation (LTP), involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3–CA1 connection naïve (nonstimulated) synapses are AMPA signaling and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test-pulse synaptic activation (AMPA silencing). To investigate to what extent LTPs at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus this early, or developmental, LTP is nothing more than an unsilencing (dedepression) and stabilization of the AMPA signaling that was lost by the prior AMPA silencing. This dedepression and stabilization of AMPA signaling was mimicked by the presence of the protein kinase A activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a “genuine” potentiation (as opposed to a dedepression) not explained by unsilencing and stabilization of AMPA-labile synapses. This “genuine,” or mature, LTP rose from close to nothing of total LTP prior to postnatal day (P)13, to about 70% of total LTP at P16, and to about 90% of total LTP at P30. Developmental LTP, by stabilization of AMPA-labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.
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Aizenman, Carlos D., and Hollis T. Cline. "Enhanced Visual Activity In Vivo Forms Nascent Synapses in the Developing Retinotectal Projection." Journal of Neurophysiology 97, no. 4 (April 2007): 2949–57. http://dx.doi.org/10.1152/jn.00452.2006.
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Patterned neural activity during development is critical for proper wiring of sensory circuits. Previous work demonstrated that exposing freely swimming Xenopus tadpoles to 4 h of enhanced visual stimulation accelerates the dendritic growth rate of optic tectal neurons in vivo. Here we test whether this same period of visual stimulation increased synaptic maturation and formation of new synapses in the retinotectal pathway. We assessed synaptic properties of stage 48 tadpoles that were exposed to a simulated-motion stimulus for 4–5 h. Based on our findings that immature retinotectal synapses have greater paired-pulse facilitation compared with more mature synapses, consistent with a lower release probability (Pr), we used a paired-pulse protocol to elicit responses selectively from nascent synapses with low Pr. Although AMPA/NMDA ratios for single and paired stimuli were the same in control tadpoles, visual stimulation caused a relative decrease in the AMPA/NMDA ratio of the paired response. We evoked retinotectal synaptic transmission in the presence of Sr2+ to record asynchronous vesicle release. We compared evoked mEPSCs induced by single and paired stimuli and found that visual stimulation selectively enhances the amplitude and number of AMPA receptor (AMPAR)–mediated mEPSCs evoked by paired stimuli relative to those evoked by single stimuli. Together these results show that enhanced visual stimulation affects both AMPAR- and NMDAR-mediated responses in a population of synapses revealed by paired-pulse stimulation. This suggests that in vivo visual stimulation increases synapses that have a low Pr and that have properties consistent with immature synapses.
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Hanley, Jonathan G. "Endosomal sorting of AMPA receptors in hippocampal neurons." Biochemical Society Transactions 38, no. 2 (March 22, 2010): 460–65. http://dx.doi.org/10.1042/bst0380460.
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An important mechanism for the regulation of excitatory synaptic transmission in the hippocampus involves tight control of AMPAR [AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor] trafficking to alter the number or subtype of synaptic receptors. This is achieved via the multiple stages of the endosomal system. AMPARs constitutively cycle through early endosomes and recycling endosomes to maintain synaptic receptor numbers. However, on induction of synaptic plasticity, subtle alterations are made to this cycle by the action of specific AMPAR-interacting proteins and also via a number of additional proteins that regulate endosomal sorting more generally. During long-term depression, receptors are diverted to late endosomes and lysosomes rather than recycling back to the plasma membrane, hence reducing the number of receptors at the synapse. The increased number of synaptic AMPARs after induction of LTP (long-term potentiation) originates from the recycling compartment. In addition, transient changes in subunit composition may arise as a result of retention of AMPAR subtypes within the endosome during LTP. Aberrant trafficking after pathological insults such as oxygen/glucose deprivation or mechanical trauma also involves alterations in synaptic AMPAR subunit composition, leading to calcium influx that ultimately results in cell death.
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Lu, Wei, John A. Gray, Adam J. Granger, Matthew J. During, and Roger A. Nicoll. "Potentiation of Synaptic AMPA Receptors Induced by the Deletion of NMDA Receptors Requires the GluA2 Subunit." Journal of Neurophysiology 105, no. 2 (February 2011): 923–28. http://dx.doi.org/10.1152/jn.00725.2010.
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Deletion of N-methyl-d-aspartate receptors (NMDARs) early in development results in an increase in the number of synaptic AMPA receptors (AMPARs), suggesting a role for NMDARs in negatively regulating AMPAR trafficking at developing synapses. Substantial evidence has shown that AMPAR subunits function differentially in AMPAR trafficking. However, the role of AMPAR subunits in the enhancement of AMPARs following NMDAR ablation remains unknown. We have now performed single-cell genetic deletions in double-floxed mice in which the deletion of GluN1 is combined with the deletion of GluA1 or GluA2. We find that the AMPAR enhancement following NMDAR deletion requires the GluA2 subunit, but not the GluA1 subunit, indicating a key role for GluA2 in the regulation of AMPAR trafficking in developing synapses.
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Benarroch, Eduardo E. "AMPA receptors." Neurology 87, no. 12 (August 24, 2016): 1281–88. http://dx.doi.org/10.1212/wnl.0000000000003138.
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Gonzalez, LC, L. Pinilla, M. Tena-Sempere, and E. Aguilar. "Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the control of prolactin, growth hormone and gonadotropin secretion in prepubertal rats." Journal of Endocrinology 162, no. 3 (September 1, 1999): 417–24. http://dx.doi.org/10.1677/joe.0.1620417.
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Excitatory amino acids, such as glutamate, constitute a major transmitter system in the control of hypothalamic-pituitary secretion. Different subtypes of glutamate receptors, such as NMDA (N-methyl-d-aspartic acid) and KA (kainate) receptors, are involved in the control of anterior pituitary secretion. Other receptor subtypes, such as AMPA (activated by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and metabotropic receptors, have been identified, although their role in the control of neuroendocrine function remains largely unknown. Recent reports have demonstrated the involvement of AMPA receptors in the control of the steroid-induced luteinizing hormone (LH) surge in female and growth hormone (GH) secretion in male rats. The aim of this study was to assess the potential role of AMPA receptors in the control of GH, prolactin (PRL), LH and follicle-stimulating hormone (FSH) secretion in prepubertal 23-day-old rats. To this end, prepubertal female rats were injected with AMPA (2.5 or 5 mg/kg i.p.) or the antagonist of AMPA receptors 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo-benzo (f) quinoxaline-7-sulfonamide (NBQX; 0.25 or 0.50 mg/kg i.p.). Serum LH and FSH concentrations and hypothalamic LH-releasing hormone (LHRH) content remained unchanged after AMPA or NBQX administration. In contrast, serum PRL levels significantly decreased 15, 30 and 60 min after i.p. administration of AMPA and increased 120 min after NBQX treatment, whereas serum GH levels increased after AMPA treatment and decreased after NBQX administration. Considering that AMPA has been shown to activate a subset of kainate receptors, its effects were compared with those elicited by 2.5 mg/kg KA in prepubertal female rats. At this age, however, KA was unable to reproduce the effects of AMPA on PRL and GH secretion, thus suggesting that the actions observed after AMPA administration were carried out specifically through AMPA receptors. In addition, as the effects of AMPA on LH secretion in adult females have been proved to be steroid-dependent, the effects of AMPA (2.5 mg/kg) and NBQX (0.5 mg/kg) were tested in prepubertal animals with different gonadal backgrounds, i.e. intact males, and intact and ovariectomized (OVX) females. The effects of AMPA in prepubertal females appeared to be modulated by ovarian secretion, as the inhibition of PRL secretion disappeared and LH secretion was partially suppressed by AMPA in OVX animals whereas the stimulatory effect on GH release was enhanced by ovariectomy. Furthermore, in male rats, AMPA administration significantly decreased PRL secretion and increased serum GH levels, the amplitude of the GH response being higher than in prepubertal females. To ascertain the pituitary component for the reported actions of AMPA, hemi-pituitaries of male rats were incubated in the presence of AMPA (10(-8)-10(-6) M). The results obtained showed no effect of AMPA on PRL, GH and gonadotropin secretion in vitro. Finally, we investigated the involvement of the dopaminergic (DA) system in the inhibitory action of AMPA on PRL secretion. Pre-treatment of prepubertal female rats with a dopamine receptor antagonist (domperidone: 1 mg/kg) resulted in the blockage of AMPA-mediated inhibition of PRL secretion, thus suggesting that this action is probably mediated by an increase in DA activity. In conclusion, we provide evidence for the physiological role of AMPA receptors in the control of PRL and GH secretion in prepubertal rats. In contrast, our data cast doubts on the involvement of AMPA receptors in the regulation of gonadotropin secretion at this age. The effects of AMPA reported herein were not mediated through activation of kainate receptors and were probably exerted at the hypothalamic or suprahypothalamic levels. In addition, we show that ovarian secretion actively modulates the effects of AMPA receptor activation on anterior pituitary secretion in prepubertal female rats.
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Gonzalez, LC, L. Pinilla, M. Tena-Sempere, and E. Aguilar. "Regulation of prolactin secretion by alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in male rats." Journal of Endocrinology 166, no. 3 (September 1, 2000): 669–75. http://dx.doi.org/10.1677/joe.0.1660669.
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The secretion of PRL is controlled by different hypothalamic signals. Depending on the experimental model, PRL secretion increases or decreases after activation of N-methyl-d -aspartic acid and kainate receptors. Recently we have described that activation of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors inhibits PRL secretion in prepubertal male rats. The aim of present study was to examine (1) the physiological relevance of this finding, (2) the possible age-related changes observed after activation or blockade of AMPA receptors, (3) the specificity of the AMPA effect, (4) the hypothalamic and/or pituitary localization of AMPA action, and (5) the mechanism(s) of action of AMPA agonists. In a first set of experiments, neonatal males (5 and 10 days old) and prepubertal (23 days old) male rats were injected with AMPA (1, 2.5 or 5 mg/kg) or the antagonist of AMPA receptors 1,2,3, 4-tetrahydro-6-nitro-2,3-dioxo-! benzo (f) quinoxaline-7-sulfonamide (NBQX; 0.25 or 0.50 mg/kg). Serum PRL concentrations decreased significantly 15 and 30 min after i.p. administration of AMPA in prepubertal male rats, while the inhibitory effect of AMPA was not observed in 5- and 10-day-old males. The effect of AMPA was abolished by NBQX but not by MK-801 (a selective antagonist of NMDA receptors). NBQX alone (0.25 or 0.50 mg/kg) had no effect on PRL release. In vitro, AMPA slightly stimulated PRL secretion by hemipituitaries from prepubertal males, suggesting that the hypothalamus is likely the site of action for the reported inhibitory action of AMPA on PRL release. In this sense, the blockade of AMPA effects in animals pretreated with domperidone (a dopaminergic antagonist) or alpha-methyl-p-tyrosine (an inhibitor of dopamine synthesis) suggests that an increase in the release of hypothalamic dopamine is probably the mechanism i! nvolved in the effect of AMPA. In a second set of experiments, the effects of AMPA (2.5 mg/kg i.p.) and NBQX (0.5 mg/kg i.p. and 20 or 40 nmol i.c.v.) were tested in freely moving adult male rats sampled during periods of 2, 3 or 6 h. In contrast with data obtained in prepubertal rats, neither AMPA nor NBQX affected PRL secretion. In conclusion, these data indicate that activation of AMPA receptors inhibits PRL secretion in prepubertal male rats. This effect probably involves the release of dopamine from the hypothalamus and disappears in adulthood.
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Jia, Zhengping, YouMing Lu, Jeff Henderson, Franco Taverna, Carmelo Romano, Wanda Abramow-Newerly, J. Martin Wojtowicz, and John Roder. "Selective Abolition of the NMDA Component of Long-Term Potentiation in Mice Lacking mGluR5." Learning & Memory 5, no. 4 (September 1, 1998): 331–43. http://dx.doi.org/10.1101/lm.5.4.331.
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The mechanisms underlying the differential expression of long-term potentiation (LTP) by AMPA and NMDA receptors, are unknown, but could involve G-protein-linked metabotropic glutamate receptors. To investigate this hypothesis we created mutant mice that expressed no metabotropic glutamate receptor 5 (mGluR5), but showed normal development. In an earlier study of these mice we analyzed field-excitatory postsynaptic potential (fEPSPs) in CA1 region of the hippocampus and found a small decrease; possibly arising from changes in the NMDAR-mediated component of synaptic transmission. In the present study we used whole-cell patch clamp recordings of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons to identify the AMPAR- and NMDAR-mediated components of LTP. Recordings from control mice following tetanus, or agonist application (IS, 3R-1-amino-cyclopentane 1,3-dicarboxylic acid) (ACPD), revealed equal enhancement of the AMPA and NMDA receptor-mediated components. In contrast, CA1 neurons from mGluR5-deficient mice showed a complete loss of the NMDA-receptor-mediated component of LTP (LTPNMDA), but normal LTP of the AMPA-receptor-mediated component (LTPAMPA). This selective loss of LTPNMDA was seen in three different genotypic backgrounds and was apparent at all holding potentials (−70 mV to +20 mV). Furthermore, the LTPNMDA deficit in mGluR5 mutant mice could be rescued by stimulating protein kinase C (PKC) with 4β-phorbol-12,13-dibutyrate (PDBu). These results suggest that PKC may couple the postsynaptic mGluR5 to the NMDA-receptor potentiation during LTP, and that this signaling mechanism is distinct from LTPAMPA. Differential enhancement of AMPAR and NMDA receptors by mGluR5 also supports a postsynaptic locus for LTP.
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MacLean, David M., Swarna S. Ramaswamy, Mei Du, James R. Howe, and Vasanthi Jayaraman. "Stargazin promotes closure of the AMPA receptor ligand-binding domain." Journal of General Physiology 144, no. 6 (November 24, 2014): 503–12. http://dx.doi.org/10.1085/jgp.201411287.
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Transmembrane AMPA receptor (AMPAR) regulatory proteins (TARPs) markedly enhance AMPAR function, altering ligand efficacy and receptor gating kinetics and thereby shaping the postsynaptic response. The structural mechanism underlying TARP effects on gating, however, is unknown. Here we find that the prototypical member of the TARP family, stargazin or γ-2, rescues gating deficits in AMPARs carrying mutations that destabilize the closed-cleft states of the ligand-binding domain (LBD), suggesting that stargazin reverses the effects of these mutations and likely stabilizes closed LBD states. Furthermore, stargazin promotes a more closed conformation of the LBD, as indicated by reduced accessibility to the large antagonist NBQX. Consistent with the functional studies, luminescence resonance energy transfer experiments directly demonstrate that the AMPAR LBD is on average more closed in the presence of stargazin, in both the apo and agonist-bound states. The additional cleft closure and/or stabilization of the more closed-cleft states of the LBD is expected to translate to higher agonist efficacy and could contribute to the structural mechanism for stargazin modulation of AMPAR function.
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Гмиро, Валерий Евгеньевич, and А. С. Жигулин. "Поиск избирательных GluA1 AMPA-блокаторов в ряду дикатионных соединений." Химико-фармацевтический журнал 56, no. 3 (April 4, 2022): 8–14. http://dx.doi.org/10.30906/0023-1134-2022-56-3-8-14.
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Синтезированы дикатионные производные на основе адамантильного и 1-фенилциклогексильнгого фрагмента. В молекулах варьировали катионные группы и расстояние между ними изменением длины углеводородной цепи (5 или 6 метиленовых звеньев). Исследовали способность дикатионов блокировать открытые каналы NMDA- и AMPA-глутаматных рецепторов. Для исследования NMDA-рецепторов опыты проводили на пирамидных нейронах поля СА1 гиппокампа. Для исследования АМРА-рецепторов, лишенных субъединицы GluA2, использовали гигантские холинергические интернейроны стриатума. Исследование связи между структурой дикатионов и их активностью привело к выявлению 5 соединений (ИЭМ-2131, ИЭМ-2132, ИЭМ-2133, ИЭМ-2041, ИЭМ-2297), которые превосходят по GluA1 AMPA-избирательности эталонный GluA1 AMPA-блокатор ИЭМ-1460. Наибольшую AMPA-активность и избирательность проявил ИЭМ-2131, который на порядок активнее ИЭМ-1460 по AMPA-блокирующей активности (ИК50, соответственно, 0,29 и 3 мкМ) и в 5 раз по AMPA-избирательности (соответственно, 101 и 500 раз). Обсуждаются клиническая перспективность GluA1 AMPA-блокаторов.
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Achzet, Lindsay M., Clara J. Davison, Moira Shea, Isabella Sturgeon, and Darrell A. Jackson. "Oxidative Stress Underlies the Ischemia/Reperfusion-Induced Internalization and Degradation of AMPA Receptors." International Journal of Molecular Sciences 22, no. 2 (January 13, 2021): 717. http://dx.doi.org/10.3390/ijms22020717.
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Stroke is the fifth leading cause of death annually in the United States. Ischemic stroke occurs when a blood vessel supplying the brain is occluded. The hippocampus is particularly susceptible to AMPA receptor-mediated delayed neuronal death as a result of ischemic/reperfusion injury. AMPA receptors composed of a GluA2 subunit are impermeable to calcium due to a post-transcriptional modification in the channel pore of the GluA2 subunit. GluA2 undergoes internalization and is subsequently degraded following ischemia/reperfusion. The subsequent increase in the expression of GluA2-lacking, Ca2+-permeable AMPARs results in excitotoxicity and eventually delayed neuronal death. Following ischemia/reperfusion, there is increased production of superoxide radicals. This study describes how the internalization and degradation of GluA1 and GluA2 AMPAR subunits following ischemia/reperfusion is mediated through an oxidative stress signaling cascade. U251-MG cells were transiently transfected with fluorescently tagged GluA1 and GluA2, and different Rab proteins to observe AMPAR endocytic trafficking following oxygen glucose-deprivation/reperfusion (OGD/R), an in vitro model for ischemia/reperfusion. Pretreatment with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP), a superoxide dismutase mimetic, ameliorated the OGD/R-induced, but not agonist-induced, internalization and degradation of GluA1 and GluA2 AMPAR subunits. Specifically, MnTMPyP prevented the increased colocalization of GluA1 and GluA2 with Rab5, an early endosomal marker, and with Rab7, a late endosomal marker, but did not affect the colocalization of GluA1 with Rab11, a marker for recycling endosomes. These data indicate that oxidative stress may play a vital role in AMPAR-mediated cell death following ischemic/reperfusion injury.
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Zhao, Jiaxiang, Zilan Yang, Brandon Alderman, and Shiqiang Zou. "(Invited) Electrooxidation Pathway and Kinetics for Aminomethyl Phosphonic Acid (AMPA) Degradation in Diluted Water Matrices." ECS Meeting Abstracts MA2022-02, no. 27 (October 9, 2022): 1060. http://dx.doi.org/10.1149/ma2022-02271060mtgabs.
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The U.S. agriculture and related industries consume 280 million pounds of glyphosate each year. Most applied glyphosate is released into the aquatic environment and biochemically transformed into Aminomethyl Phosphonic Acid (AMPA). The generated AMPA can trigger eutrophication, bioaccumulation in food webs, potential cell damage, and embryonic mortality in living organisms. To effectively control AMPA, biological retention systems (e.g., wetlands) have been utilized to degrade AMPA. However, bioretention systems are characterized by slow degradation kinetics, a large footprint, and low resilience toward shock loads. This study proposes an alternative electrooxidation system as an abiotic, chemical-free approach to transforming organic AMPA into easy-to-separate inorganic phosphate. Our system selected a boron-doped diamond as the anode due to its wide electrochemical window and high electrochemical stability. We comprehensively explored AMPA degradation pathway, kinetics, and system energy requirement in diluted water matrices. Initial 24-h batch tests revealed more than 83% of 0.01-mM AMPA were electrooxidized by hydroxyl radicals under a chronoamperometry mode. The highest oxidation rate could reach 12 mmol AMPA m-2 h-1 in the first 6 hours. The oxidation end products are determined to be CO2, NH4 +, and PO4 3-, indicating complete mineralization of organic C, N, and P within AMPA molecules. We further evaluated three electrooxidation operating modes, including chronoamperometry (CA), chronopotentiometry (CP), and applied voltage (AV). All three operating modes exhibited >80% AMPA oxidation in 24 hours. Eventually, we selected the AV mode for a subsequent long-term test due to its higher compatibility with on-site applications. During this 30-day operation, our flow-through electrooxidation system was operated under a hydraulic retention time of 3-12 hours and was able to degrade a maximum AMPA loading of 12 mmol AMPA m-2 h-1. Our promising results confirm the capability of our electrochemical retention system to degrade AMPA in diluted water matrices and warrant future efforts to probe parasitic reactions for reduced system energy input.
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Venkataramani, Varun, Dimitar Tanev, Christopher Strahle, Alexander Studier-Fischer, Laura Fankhauser, Tobias Kessler, Maria Losada Perez, et al. "TMIC-27. GLUTAMATERGIC NEURON-GLIOMA SYNAPSES DRIVE BRAIN TUMOUR PROGRESSION." Neuro-Oncology 21, Supplement_6 (November 2019): vi253. http://dx.doi.org/10.1093/neuonc/noz175.1061.
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Abstract A network of communicating tumour cells established by tumour microtubes (TMs) is supposed to mediate relevant aspects of progression and resistance of incurable gliomas. Moreover, neuronal activity has been shown to foster malignant behavior of glioma cells by non-synaptic paracrine and autocrine mechanisms. Here, we report an unexpected direct communication channel between neurons and glioma cells in multiple disease models as well as in astrocytomas and glioblastomas (GBs) of adult patients: functional bona fide chemical synapses formed between presynaptic neurons and postsynaptic glioma cells. These neurogliomal synapses (NGS) show a typical synaptic ultrastructure, are located on TM networks, and produce depolarizing postsynaptic currents mediated by glutamate receptors of the AMPA subtype. AMPA-type glutamate receptors (AMPAR) are expressed by a molecularly and morphologically distinct subpopulation of network-integrated glioma cells. Increased neuronal activity under epileptic conditions ex vivo or neuronal optogenetic stimulation in vivo enhanced, while general anesthesia diminished synchronized calcium transients in TM-connected glioma networks. Accordingly, anesthesia reduced invasiveness of TM-positive tumour cells in mice. Genetic perturbation of AMPAR or chronic AMPAR inhibition by perampanel decreased glioma invasion and proliferation in mice and deletion of GluRII in Drosophila glioma increased survival. These findings reveal a hitherto unappreciated direct synaptic communication between neurons and glioma cells that appears relevant for brain tumour biology, implying new avenues for glioma treatment.
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Wang, Sabrina, Zhengping Jia, John Roder, and Timothy H. Murphy. "AMPA Receptor-Mediated Miniature Synaptic Calcium Transients in GluR2 Null Mice." Journal of Neurophysiology 88, no. 1 (July 1, 2002): 29–40. http://dx.doi.org/10.1152/jn.2002.88.1.29.
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AMPA-type glutamate receptors are normally Ca2+ impermeable due to the expression of the GluR2 receptor subunit. By using GluR2 null mice we were able to detect miniature synaptic Ca2+ transients (MSCTs) associated with AMPA-type receptor-mediated miniature synaptic currents at single synapses in primary cortical cultures. MSCTs and associated Ca2+ transients were monitored under conditions that isolated responses mediated by AMPA or N-methyl-d-aspartate (NMDA) receptors. As expected, addition of the antagonist 6-cyano-7-nitroquinoxalene-2,3-dione (CNQX, 3 μM) blocked the AMPA receptor-mediated MSCTs. Voltage-gated Ca2+channels did not contribute to AMPA MSCTs because CdCl2 (0.1–0.2 mM) did not significantly alter the frequency or the amplitude of the MSCTs. The amplitude of AMPA MSCTs appeared to be regulated independently from event frequency since the two measures were not correlated ( R = 0.023). Synapses were identified that only expressed MSCTs attributed to either NMDA or AMPA receptors. At synapses with only NMDA responses, MSCT amplitude was significantly lower (by 40%) than synapses expressing both NMDA and AMPA responses. At synapses that showed MSCTs mediated by both AMPA and NMDA receptors, the amplitude of the transients in each condition was positively correlated ( R = 0.94). Our results suggest that when AMPA and NMDA receptors are co-expressed at synapses, mechanisms exist to ensure proportional scaling of each receptor type that are distinct from the presynaptic factors controlling the frequency of miniature release.
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Tomita, Susumu, Lu Chen, Yoshimi Kawasaki, Ronald S. Petralia, Robert J. Wenthold, Roger A. Nicoll, and David S. Bredt. "Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins." Journal of Cell Biology 161, no. 4 (May 26, 2003): 805–16. http://dx.doi.org/10.1083/jcb.200212116.
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Functional expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in cerebellar granule cells requires stargazin, a member of a large family of four-pass transmembrane proteins. Here, we define a family of transmembrane AMPA receptor regulatory proteins (TARPs), which comprise stargazin, γ-3, γ-4, and γ-8, but not related proteins, that mediate surface expression of AMPA receptors. TARPs exhibit discrete and complementary patterns of expression in both neurons and glia in the developing and mature central nervous system. In brain regions that express multiple isoforms, such as cerebral cortex, TARP–AMPA receptor complexes are strictly segregated, suggesting distinct roles for TARP isoforms. TARPs interact with AMPA receptors at the postsynaptic density, and surface expression of mature AMPA receptors requires a TARP. These studies indicate a general role for TARPs in controlling synaptic AMPA receptors throughout the central nervous system.
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Lei, Saobo, Beverley A. Orser, Gregory R. L. Thatcher, James N. Reynolds, and John F. MacDonald. "Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons." Journal of Neurophysiology 85, no. 5 (May 1, 2001): 2030–38. http://dx.doi.org/10.1152/jn.2001.85.5.2030.
Full textAbstract:
Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC50 of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.
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Ceprian, Maria, and Daniel Fulton. "Glial Cell AMPA Receptors in Nervous System Health, Injury and Disease." International Journal of Molecular Sciences 20, no. 10 (May 17, 2019): 2450. http://dx.doi.org/10.3390/ijms20102450.
Full textAbstract:
Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function. Alpha-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA)-type glutamate receptors (AMPAR) are a central mediator of glutamatergic excitatory synaptic transmission, yet they are also expressed in a wide range of glial cells where they influence a variety of important cellular functions. AMPAR enable glial cells to sense the activity of neighbouring axons and synapses, and as such many aspects of glial cell development and function are influenced by the activity of neural circuits. However, these AMPAR also render glia sensitive to elevations of the extracellular concentration of glutamate, which are associated with a broad range of pathological conditions. Excessive activation of AMPAR under these conditions may induce excitotoxic injury in glial cells, and trigger pathophysiological responses threatening other neural cells and amplifying ongoing disease processes. The aim of this review is to gather information on AMPAR function from across the broad diversity of glial cells, identify their contribution to pathophysiological processes, and highlight new areas of research whose progress may increase our understanding of nervous system dysfunction and disease.
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Bigge, Christopher F., Peter A. Boxer, and Daniel F. Ortwine. "AMPA/Kainate Receptors." Current Pharmaceutical Design 2, no. 4 (August 1996): 397–412. http://dx.doi.org/10.2174/1381612802666220925204342.
Full textAbstract:
AMPA and kainate receptors belong to a common family of ionotropic glutamate receptors. Molecular biology has revealed some of the molecular features that are responsible for selective ion permeability of the receptor comp.lex. The diversity of subunits and their combination into hetero-oligomeric recep or complexes have provided evidence that several subtypes of AMPA/kainate receptors exist within the central nervous system. AMPA (2) and kainic acid (4) are agonists that have been used to define receptor pharmacology, including the issue of receptor desensitization and its relationship to excitotoxicity. Selective AMPA antagonists, such as NBQX (9), and mixed AMPA and NMDA glycine site (GlyN) antagonists, such as PNQX (11), have demonstrated significant neuroprotection in several models of cerebral ischemia and neuronal injury, and have provided the basis for extensive research into this mechanism for neuroprotection by the pharmaceutical industry. Physicochemical properties including poor aqueous solubility and high crystallinity of quinoxalinedione-based molecules have hampered their development. Pharmacophore models of the AMPA recognition site have been generated that are useful for identifying molecular features that may circumvent those issues. Alternative templates have been investigated that are hoped to retain intrinsic affinity at the glutamate recognition site of AMPA/kainate receptors comparable or superior to that of 9 and 11. Noncompetitive antagonists of AMPA receptor function may have a therapeutic advantage in that they will not be reversed by a pool of excess glutamate that is associated with neuronal injury or ischemia. Compounds based upon the 2,3- benzodiazepine analog, GYKI 52466 (28) are reported to have significant neuroprotective and anticonvulsant properties. There is evidence that positive modulation of AMPA/kainate receptors may be useful for improving memory formation·and cognitive abilities. Analogs of cyclothiazide (27) and aniracetam (31) have been investigated to delay or reverse cognitive deficits associated with neurodegenerative diseases. The molecules that are discussed herein are a first generation of agents that modulate and have helped to define AMPA/kainate receptor function. It is expected that a second generation of agents will provide clinical utility in a number of neurological disorders, and provide further insight into the functional activity of receptor subtypes.
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Qneibi, Mohammad, Safa’ Nassar, Sosana Bdir, and Adel Hidmi. "α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors’ Gating Modules." Cells 11, no. 22 (November 15, 2022): 3608. http://dx.doi.org/10.3390/cells11223608.
Full textAbstract:
The ionotropic glutamate receptor subtype α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) is responsible for most excitatory transmission in the brain. AMPA receptor function is altered in numerous neurological illnesses, making AMPA receptors appealing therapeutic targets for clinical intervention. Alpha-Lipoic acid (α-LA) is a naturally occurring compound, which functions as a co-factor in metabolism and energy production. α-LA is an antioxidant with various benefits in treating diabetes, including managing symptomatic diabetic neuropathy. This study will test a novel and innovative strategy to synthesize a new isomer of lipoic acid (R-LA) derivatives (bifunctional NO-donor/antioxidant) in one chemical on homomeric and heteromeric AMPA receptor subunits. We used patch-clamp electrophysiology to examine LA derivatives expressed in human embryonic kidney 293 cells (HEK293) for inhibition and changes in desensitization or deactivation rates. LA derivatives were shown to be potent antagonists of AMPA receptors, with an 8–11-fold reduction in AMPA receptor currents seen following the delivery of the compounds. Furthermore, the LA derivatives influenced the rates of desensitization and deactivation of AMPA receptors. Based on our results, especially given that α-LA is closely connected to the nervous system, we may better understand using AMPA receptors and innovative drugs to treat neurological diseases associated with excessive activation of AMPA receptors.
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Twomey, Edward C., Maria V. Yelshanskaya, and Alexander I. Sobolevsky. "Structural and functional insights into transmembrane AMPA receptor regulatory protein complexes." Journal of General Physiology 151, no. 12 (October 15, 2019): 1347–56. http://dx.doi.org/10.1085/jgp.201812264.
Full textAbstract:
Fast excitatory neurotransmission is mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype of ionotropic glutamate receptor (AMPAR). AMPARs initiate depolarization of the postsynaptic neuron by allowing cations to enter through their ion channel pores in response to binding of the neurotransmitter glutamate. AMPAR function is dramatically affected by auxiliary subunits, which are regulatory proteins that form various complexes with AMPARs throughout the brain. The most well-studied auxiliary subunits are the transmembrane AMPAR regulatory proteins (TARPs), which alter the assembly, trafficking, localization, kinetics, and pharmacology of AMPARs. Recent structural and functional studies of TARPs and the TARP-fold germ cell-specific gene 1-like (GSG1L) subunit have provided important glimpses into how auxiliary subunits regulate the function of synaptic complexes. In this review, we put these recent structures in the context of new functional findings in order to gain insight into the determinants of AMPAR regulation by TARPs. We thus reveal why TARPs display a broad range of effects despite their conserved modular architecture.
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Zhang, Jifeng, Yichen Yin, Zhisheng Ji, Zhenbin Cai, Bo Zhao, Jiong Li, Minghui Tan, and Guoqing Guo. "Endophilin2 Interacts with GluA1 to Mediate AMPA Receptor Endocytosis Induced by Oligomeric Amyloid-β." Neural Plasticity 2017 (2017): 1–11. http://dx.doi.org/10.1155/2017/8197085.
Full textAbstract:
Amyloid-β(Aβ) plays an important role in Alzheimer’s disease (AD), as oligomeric Aβinduces loss of postsynaptic AMPA receptors (AMPARs) leading to cognitive deficits. The loss of postsynaptic AMPARs is mediated through the clathrin-dependent endocytosis pathway, in which endophilin2 is one of the important regulatory proteins. Endophilin2, which is enriched in both the pre- and postsynaptic membrane, has previously been reported to be important for recycling of synaptic vesicles at the presynaptic membrane. However, the role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR endocytosis is not well understood. In this study, we show that endophilin2 does not affect constitutive AMPAR endocytosis. Endophilin2 knockdown, but not overexpression, resisted oligomeric Aβ-induced AMPAR dysfunction. Moreover, endophilin2 colocalized and interacted with GluA1, a subunit of AMPAR, to regulate oligomeric Aβ-induced AMPAR endocytosis. Thus, we have determined a role of endophilin2 in oligomeric Aβ-induced postsynaptic AMPAR dysfunction, indicating possible directions for preventing the loss of AMPARs in cognitive impairment and providing evidence for the clinical treatment of AD.
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Dias, Ana Carolina Rodrigues, and Eduardo Colombari. "Central nitric oxide modulates hindquarter vasodilation elicited by AMPA receptor stimulation in the NTS of conscious rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 5 (May 2006): R1330—R1336. http://dx.doi.org/10.1152/ajpregu.00150.2005.
Full textAbstract:
Microinjection of S-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) in the nucleus of the solitary tract (NTS) of conscious rats causes hypertension, bradycardia, and vasoconstriction in the renal, mesenteric, and hindquarter vascular beds. In the hindquarter, the initial vasoconstriction is followed by vasodilation with AMPA doses >5 pmol/100 nl. To test the hypothesis that this vasodilation is caused by activation of a nitroxidergic pathway in the NTS, we examined the effect of pretreatment with the nitric oxide synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 10 nmol/100 nl, microinjected into the NTS) on changes in mean arterial pressure, heart rate, and regional vascular conductance (VC) induced by microinjection of AMPA (10 pmol/100 nl in the NTS) in conscious rats. AMPA increased hindquarter VC by 18 ± 4%, but after pretreatment with l-NAME, AMPA reduced hindquarter VC by 16 ± 7% and 17 ± 9% (5 and 15 min after pretreatment, P < 0.05 compared with before pretreatment). Pretreatment with l-NAME reduced AMPA-induced bradycardia from 122 ± 40 to 92 ± 32 beats/min but did not alter the hypertension induced by AMPA (35 ± 5 mmHg before pretreatment, 43 ± 6 mmHg after pretreatment). Control injections with d-NAME did not affect resting values or the response to AMPA. The present study shows that stimulation of AMPA receptors in the NTS activates both vasodilatatory and vasoconstrictor mechanisms and that the vasodilatatory mechanism depends on production of nitric oxide in the NTS.
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Morsette, Delmore J., Hanna Sidorowicz, and Celia D. Sladek. "Role of non-NMDA receptors in vasopressin and oxytocin release from rat hypothalamo-neurohypophysial explants." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 280, no. 2 (February 1, 2001): R313—R322. http://dx.doi.org/10.1152/ajpregu.2001.280.2.r313.
Full textAbstract:
Glutamate is recognized as a prominent excitatory transmitter in the supraoptic nucleus (SON) and is involved in transmission of osmoregulatory information from the osmoreceptors to the vasopressin (VP) and oxytocin (OT) neurons. Explants of the hypothalamo-neurohypophysial system were utilized to characterize the roles of the non- N-methyl-d-aspartate (NMDA) glutamate receptor subtypes (non-NMDA-Rs), kainic acid receptors (KA-Rs), and aminopropionic acid receptors (AMPA-Rs) and to evaluate the interdependence of NMDA-Rs and non-NMDA-Rs in eliciting hormone release. Although both KA and AMPA increased hormone release, a specific agonist of the KA-Rs, SYM-2081, was not effective. This combined with the finding that cyclothiazide, an agent that inhibits the desensitization of AMPA-Rs, increased the VP response to both KA and AMPA indicates that the increase in hormone release induced by the non-NMDA agonists is mediated via AMPA-Rs, rather than KA-Rs. Inhibition of osmotically stimulated VP and OT release by a specific AMPA-R antagonist indicated that AMPA-Rs are essential for mediating osmotically stimulated hormone release. NMDA-stimulated VP but not OT release was prevented by blockade of non-NMDA-Rs, but AMPA-stimulated VP/OT release was not prevented by NMDA-R blockade.
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SHEN, WEN, SARAH G. FINNEGAN, and MALCOLM M. SLAUGHTER. "Glutamate receptor subtypes in human retinal horizontal cells." Visual Neuroscience 21, no. 1 (January 2004): 89–95. http://dx.doi.org/10.1017/s0952523804041094.
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Glutamate receptor currents were examined in horizontal cells from cultured human retina using whole-cell recording procedures. Horizontal cells possess both AMPA and kainate receptors and both produce significant sustained currents. The kainate-induced current did not show significant desensitization and was not enhanced by concanavalin A. The sustained AMPA current was smaller than the kainate current, but the difference was almost entirely due to pronounced desensitization. The horizontal cell AMPA current was enhanced by cyclothiazide but not by PEPA, indicating the presence of the flip receptor variant. GYKI-52466 blocked the AMPA response (IC50= 5 μM against 100 μM AMPA) but also blocked the kainate response (IC50= 45 μM against 100 μM kainate). The diversity of glutamate receptors in human horizontal cells suggests that synaptic input to these neurons may be multiplexed through both kainate and AMPA channels.