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Journal articles on the topic 'GluK1 receptors'

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Author: Grafiati
Published: 14 March 2023

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1

Chałupnik, Paulina, Alina Vialko, Darryl S. Pickering, Markus Hinkkanen, Stephanie Donbosco, Thor C. Møller, Anders A. Jensen, et al. "Discovery of the First Highly Selective Antagonist of the GluK3 Kainate Receptor Subtype." International Journal of Molecular Sciences 23, no. 15 (August 8, 2022): 8797. http://dx.doi.org/10.3390/ijms23158797.

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Kainate receptors belong to the family of glutamate receptors ion channels, which are responsible for the majority of rapid excitatory synaptic transmission in the central nervous system. The therapeutic potential of kainate receptors is still poorly understood, which is also due to the lack of potent and subunit-selective pharmacological tools. In search of selective ligands for the GluK3 kainate receptor subtype, a series of quinoxaline-2,3-dione analogues was synthesized and pharmacologically characterized at selected recombinant ionotropic glutamate receptors. Among them, compound 28 was found to be a competitive GluK3 antagonist with submicromolar affinity and unprecedented high binding selectivity, showing a 400-fold preference for GluK3 over other homomeric receptors GluK1, GluK2, GluK5 and GluA2. Furthermore, in functional assays performed for selected metabotropic glutamate receptor subtypes, 28 did not show agonist or antagonist activity. The molecular determinants underlying the observed affinity profile of 28 were analyzed using molecular docking and molecular dynamics simulations performed for individual GluK1 and GluK3 ligand-binding domains.
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2

Jaremko, William, Zhen Huang, Nicholas Karl, Vincen D. Pierce, Janet Lynch, and Li Niu. "A kainate receptor–selective RNA aptamer." Journal of Biological Chemistry 295, no. 19 (March 11, 2020): 6280–88. http://dx.doi.org/10.1074/jbc.ra119.011649.

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Kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are two major, closely related receptor subtypes in the glutamate ion channel family. Excessive activities of these receptors have been implicated in a number of central nervous system diseases. Designing potent and selective antagonists of these receptors, especially of kainate receptors, is useful for developing potential treatment strategies for these neurological diseases. Here, we report on two RNA aptamers designed to individually inhibit kainate and AMPA receptors. To improve the biostability of these aptamers, we also chemically modified these aptamers by substituting their 2′-OH group with 2′-fluorine. These 2′-fluoro aptamers, FB9s-b and FB9s-r, were markedly resistant to RNase-catalyzed degradation, with a half-life of ∼5 days in rat cerebrospinal fluid or serum-containing medium. Furthermore, FB9s-r blocked AMPA receptor activity. Aptamer FB9s-b selectively inhibited GluK1 and GluK2 kainate receptor subunits, and also GluK1/GluK5 and GluK2/GluK5 heteromeric kainate receptors with equal potency. This inhibitory profile makes FB9s-b a powerful template for developing tool molecules and drug candidates for treatment of neurological diseases involving excessive activities of the GluK1 and GluK2 subunits.
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3

Sheng, Nengyin, Yun Stone Shi, and Roger A. Nicoll. "Amino-terminal domains of kainate receptors determine the differential dependence on Neto auxiliary subunits for trafficking." Proceedings of the National Academy of Sciences 114, no. 5 (January 18, 2017): 1159–64. http://dx.doi.org/10.1073/pnas.1619253114.

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The kainate receptor (KAR), a subtype of glutamate receptor, mediates excitatory synaptic responses at a subset of glutamatergic synapses. However, the molecular mechanisms underlying the trafficking of its different subunits are poorly understood. Here we use the CA1 hippocampal pyramidal cell, which lacks KAR-mediated synaptic currents, as a null background to determine the minimal requirements for the extrasynaptic and synaptic expression of the GluK2 subunit. We find that the GluK2 receptor itself, in contrast to GluK1, traffics to the neuronal surface and synapse efficiently and the auxiliary subunits Neto1 and Neto2 caused no further enhancement of these two trafficking processes. However, the regulation of GluK2 biophysical properties by Neto proteins is the same as that of GluK1. We further determine that it is the amino-terminal domains (ATDs) of GluK1 and GluK2 that control the strikingly different trafficking properties between these two receptors. Moreover, the ATDs are critical for synaptic expression of heteromeric receptors at mossy fiber–CA3 synapses and also mediate the differential dependence on Neto proteins for surface and synaptic trafficking of GluK1 and GluK2. These results highlight the fundamental differences between the two major KAR subunits and their interplay with Neto auxiliary proteins.
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4

Pollok, Stefan, and Andreas Reiner. "Subunit-selective iGluR antagonists can potentiate heteromeric receptor responses by blocking desensitization." Proceedings of the National Academy of Sciences 117, no. 41 (September 30, 2020): 25851–58. http://dx.doi.org/10.1073/pnas.2007471117.

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Ionotropic glutamate receptors (iGluRs) are key molecules for synaptic signaling in the central nervous system, which makes them promising drug targets. Intensive efforts are being devoted to the development of subunit-selective ligands, which should enable more precise pharmacologic interventions while limiting the effects on overall neuronal circuit function. However, many AMPA and kainate receptor complexes in vivo are heteromers composed of different subunits. Despite their importance, little is known about how subunit-selective ligands affect the gating of heteromeric iGluRs, namely their activation and desensitization properties. Using fast ligand application experiments, we studied the effects of competitive antagonists that block glutamate from binding at part of the four subunits. We found that UBP-310, a kainate receptor antagonist with high selectivity for GluK1 subunits, reduces the desensitization of GluK1/GluK2 heteromers and fully abolishes the desensitization of GluK1/GluK5 heteromers. This effect is mirrored by subunit-selective agonists and heteromeric receptors that contain binding-impaired subunits, as we show for both kainate and GluA2 AMPA receptors. These findings are consistent with a model in which incomplete agonist occupancy at the four receptor subunits can provide activation without inducing desensitization. However, we did not detect significant steady-state currents during UBP-310 dissociation from GluK1 homotetramers, indicating that antagonist dissociation proceeds in a nonuniform and cooperativity-driven manner, which disfavors nondesensitizing occupancy states. Besides providing mechanistic insights, these results have direct implications for the use of subunit-selective antagonists in neuroscience research and envisioned therapeutic interventions.
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5

Jaremko, William J., Zhen Huang, Wei Wen, Andrew Wu, Nicholas Karl, and Li Niu. "Identification and characterization of RNA aptamers: A long aptamer blocks the AMPA receptor and a short aptamer blocks both AMPA and kainate receptors." Journal of Biological Chemistry 292, no. 18 (March 21, 2017): 7338–47. http://dx.doi.org/10.1074/jbc.m116.774752.

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AMPA and kainate receptors, along with NMDA receptors, represent different subtypes of glutamate ion channels. AMPA and kainate receptors share a high degree of sequence and structural similarities, and excessive activity of these receptors has been implicated in neurological diseases such as epilepsy. Therefore, blocking detrimental activity of both receptor types could be therapeutically beneficial. Here, we report the use of an in vitro evolution approach involving systematic evolution of ligands by exponential enrichment with a single AMPA receptor target (i.e. GluA1/2R) to isolate RNA aptamers that can potentially inhibit both AMPA and kainate receptors. A full-length or 101-nucleotide (nt) aptamer selectively inhibited GluA1/2R with a KI of ∼5 μm, along with GluA1 and GluA2 AMPA receptor subunits. Of note, its shorter version (55 nt) inhibited both AMPA and kainate receptors. In particular, this shorter aptamer blocked equally potently the activity of both the GluK1 and GluK2 kainate receptors. Using homologous binding and whole-cell recording assays, we found that an RNA aptamer most likely binds to the receptor's regulatory site and inhibits it noncompetitively. Our results suggest the potential of using a single receptor target to develop RNA aptamers with dual activity for effectively blocking both AMPA and kainate receptors.
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Koga, Kohei, Su-Eon Sim, Tao Chen, Long-Jun Wu, Bong-Kiun Kaang, and Min Zhuo. "Kainate receptor-mediated synaptic transmissions in the adult rodent insular cortex." Journal of Neurophysiology 108, no. 7 (October 1, 2012): 1988–98. http://dx.doi.org/10.1152/jn.00453.2012.

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Kainate (KA) receptors are expressed widely in the central nervous system and regulate both excitatory and inhibitory synaptic transmission. KA receptors play important roles in fear memory, anxiety, and pain. However, little is known about their function in synaptic transmission in the insular cortex (IC), a critical region for taste, memory, and pain. Using whole cell patch-clamp recordings, we have shown that KA receptors contribute to fast synaptic transmission in neurons in all layers of the IC. In the presence of the GABAA receptor antagonist picrotoxin, the NMDA receptor antagonist AP-5, and the selective AMPA receptor antagonist GYKI 53655, KA receptor-mediated excitatory postsynaptic currents (KA EPSCs) were revealed. We found that KA EPSCs are ∼5–10% of AMPA/KA EPSCs in all layers of the adult mouse IC. Similar results were found in adult rat IC. KA EPSCs had a significantly slower rise time course and decay time constant compared with AMPA receptor-mediated EPSCs. High-frequency repetitive stimulations at 200 Hz significantly facilitated the summation of KA EPSCs. In addition, genetic deletion of GluK1 or GluK2 subunit partially reduced postsynaptic KA EPSCs, and exposure of GluK2 knockout mice to the selective GluK1 antagonist UBP 302 could significantly reduce the KA EPSCs. These data suggest that both GluK1 and GluK2 play functional roles in the IC. Our study may provide the synaptic basis for the physiology and pathology of KA receptors in the IC-related functions.
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7

Anna Kaczor, Agnieszka, Christiane Kronbach, Klaus Unverferth, Kalevi Pihlaja, Kirsti Wiinamaki, Jari Sinkkonen, Urszula Kijkowska-Murak, Tomasz Wrobel, Tomasz Stachal, and Dariusz Matosiuk. "Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors." Letters in Drug Design & Discovery 9, no. 10 (December 1, 2012): 891–98. http://dx.doi.org/10.2174/157018012804586978.

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8

Anna Kaczor, Agnieszka, Christiane Kronbach, Klaus Unverferth, Kalevi Pihlaja, Kirsti Wiinamaki, Jari Sinkkonen, Urszula Kijkowska-Murak, Tomasz Wrobel, Tomasz Stachal, and Dariusz Matosiuk. "Novel Non-Competitive Antagonists of Kainate GluK1/GluK2 Receptors." Letters in Drug Design & Discovery 9, no. 10 (October 24, 2012): 891–98. http://dx.doi.org/10.2174/1570180811209050891.

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9

Masocha, Willias. "Astrocyte activation in the anterior cingulate cortex and altered glutamatergic gene expression during paclitaxel-induced neuropathic pain in mice." PeerJ 3 (October 22, 2015): e1350. http://dx.doi.org/10.7717/peerj.1350.

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Spinal astrocyte activation contributes to the pathogenesis of paclitaxel-induced neuropathic pain (PINP) in animal models. We examined glial fibrillary acidic protein (GFAP; an astrocyte marker) immunoreactivity and gene expression of GFAP, glutamate transporters and receptor subunits by real time PCR in the anterior cingulate cortex (ACC) at 7 days post first administration of paclitaxel, a time point when mice had developed thermal hyperalgesia. The ACC, an area in the brain involved in pain perception and modulation, was chosen because changes in this area might contribute to the pathophysiology of PINP. GFAP transcripts levels were elevated by more than fivefold and GFAP immunoreactivity increased in the ACC of paclitaxel-treated mice. The 6 glutamate transporters (GLAST, GLT-1 EAAC1, EAAT4, VGLUT-1 and VGLUT-2) quantified were not significantly altered by paclitaxel treatment. Of the 12 ionotropic glutamate receptor subunits transcripts analysed 6 (GLuA1, GLuA3, GLuK2, GLuK3, GLuK5 and GLuN1) were significantly up-regulated, whereas GLuA2, GLuK1, GLuK4, GLuN2A and GLuN2B were not significantly altered and GLuA4 was lowly expressed. Amongst the 8 metabotropic receptor subunits analysed only mGLuR8 was significantly elevated. In conclusion, during PINP there is astrocyte activation, with no change in glutamate transporter expression and differential up-regulation of glutamate receptor subunits in the ACC. Thus, targeting astrocyte activation and the glutamatergic system might be another therapeutic avenue for management of PINP.
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10

Bartyzel, Agata, Agnieszka A. Kaczor, Ghodrat Mahmoudi, Ardavan Masoudiasl, Tomasz M. Wróbel, Monika Pitucha, and Dariusz Matosiuk. "Experimental and Computational Structural Studies of 2,3,5-Trisubstituted and 1,2,3,5-Tetrasubstituted Indoles as Non-Competitive Antagonists of GluK1/GluK2 Receptors." Molecules 27, no. 8 (April 12, 2022): 2479. http://dx.doi.org/10.3390/molecules27082479.

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The blockade of kainate receptors, in particular with non-competitive antagonists, has—due to their anticonvulsant and neuroprotective properties—therapeutic potential in many central nervous system (CNS) diseases. Deciphering the structural properties of kainate receptor ligands is crucial to designing medicinal compounds that better fit the receptor binding pockets. In light of that fact, here, we report experimental and computational structural studies of four indole derivatives that are non-competitive antagonists of GluK1/GluK2 receptors. We used X-ray studies and Hirshfeld surface analysis to determine the structure of the compounds in the solid state and quantum chemical calculations to compute HOMO and LUMO orbitals and the electrostatic potential. Moreover, non-covalent interaction maps were also calculated. It is worth emphasizing that compounds 3 and 4 are achiral molecules crystallising in non-centrosymmetric space groups, which is a relatively rare phenomenon.
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11

Solly, Kelli, Rebecca Klein, Michael Rudd, M. Katharine Holloway, Eric N. Johnson, Darrell Henze, and Michael F. A. Finley. "High-Throughput Screen of GluK1 Receptor Identifies Selective Inhibitors with a Variety of Kinetic Profiles Using Fluorescence and Electrophysiology Assays." Journal of Biomolecular Screening 20, no. 6 (February 19, 2015): 708–19. http://dx.doi.org/10.1177/1087057115570580.

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GluK1, a kainate subtype of ionotropic glutamate receptors, exhibits an expression pattern in the CNS consistent with involvement in pain processing and migraine. Antagonists of GluK1 have been shown to reduce pain signaling in the spinal cord and trigeminal nerve, and are predicted to provide pain and migraine relief. We developed an ultra-high-throughput small-molecule screen to identify antagonists of GluK1. Using the calcium indicator dye fluo-4, a multimillion-member small-molecule library was screened in 1536-well plate format on the FLIPR (Fluorescent Imaging Plate Reader) Tetra against cells expressing a calcium-permeable GluK1. Following confirmation in the primary assay and subsequent counter-screen against the endogenous Par-1 receptor, 6100 compounds were selected for dose titration to assess potency and selectivity. Final triage of 1000 compounds demonstrating dose-dependent inhibition with IC50 values of less than 12 µM was performed in an automated whole-cell patch clamp electrophysiology assay. Although a weak correlation between electrophysiologically active and calcium-imaging active compounds was observed, the identification of electrophysiologically active compounds with a range of kinetic profiles revealed a broad spectrum of mechanisms of action.
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12

Descalzi, Giannina, Tao Chen, Kohei Koga, Xiang-Yao Li, Kaori Yamada, and Min Zhuo. "Cortical GluK1 kainate receptors modulate scratching in adult mice." Journal of Neurochemistry 126, no. 5 (July 19, 2013): 636–50. http://dx.doi.org/10.1111/jnc.12351.

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13

Karim, Mohammad Rabiul, Munmun Pervin, and Yasuro Atoji. "Glutamatergic circuits in the song system of Zebra Finch brain determined by gene expression of Vglut2 and Glutamate receptors." Research in Agriculture Livestock and Fisheries 1, no. 1 (February 22, 2015): 61–70. http://dx.doi.org/10.3329/ralf.v1i1.22356.

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The songbird brain has a system of interconnected nuclei that are specialized for singing and song learning. Electrophysiological findings indicate a role for the glutamatergic neurons in the song system. Vesicular glutamate transporter 2 (vGluT2) is considered to be a specific biomarker of glutamatergic neurons in birds. Neurons receiving glutamatergic afferents express mRNA of ionotropic glutamate receptor subunits. This study examined expression of vGluT2 and glutamate receptor subunit mRNAs in nuclei of the song pathways of male zebra finch brain by in situ hybridization. VGluT2 mRNA was revealed high density of expression in the song nuclei, namely HVC, lateral magnocellular nucleus of the anterior nidopallium, and robust nucleus of the arcopallium. Area X did not show expression of vGluT2 mRNA. Nuclei in the descending motor pathway (dorsomedial nucleus of the intercollicular complex and retroambigual nucleus) were expressed vGluT2 mRNA. Target nuclei of vGluT2 mRNA-expressing nuclei showed hybridization signals for mRNAs of ionotropic glutamate receptor subunits. At least one of five subunit mRNAs (GluA1, GluA4, GluK1, GluN1, GluN2A) was expressed in song nuclei. The present findings support the existence of glutamatergic circuits in the song system in songbirds. DOI: http://dx.doi.org/10.3329/ralf.v1i1.22356 Res. Agric., Livest. Fish.1(1): 61-70, Dec 2014
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14

Kaczor, Agnieszka A., Zbigniew Karczmarzyk, Andrzej Fruziński, Kalevi Pihlaja, Jari Sinkkonen, Kirsti Wiinämaki, Christiane Kronbach, Klaus Unverferth, Antti Poso, and Dariusz Matosiuk. "Structural studies, homology modeling and molecular docking of novel non-competitive antagonists of GluK1/GluK2 receptors." Bioorganic & Medicinal Chemistry 22, no. 2 (January 2014): 787–95. http://dx.doi.org/10.1016/j.bmc.2013.12.013.

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15

Fritsch, B., J. Reis, M. Gasior, R. M. Kaminski, and M. A. Rogawski. "Role of GluK1 Kainate Receptors in Seizures, Epileptic Discharges, and Epileptogenesis." Journal of Neuroscience 34, no. 17 (April 23, 2014): 5765–75. http://dx.doi.org/10.1523/jneurosci.5307-13.2014.

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16

Fisher, Janet L. "The auxiliary subunits Neto1 and Neto2 have distinct, subunit-dependent effects at recombinant GluK1- and GluK2-containing kainate receptors." Neuropharmacology 99 (December 2015): 471–80. http://dx.doi.org/10.1016/j.neuropharm.2015.08.018.

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17

Bartyzel, Agata, Agnieszka A. Kaczor, Halina Głuchowska, Monika Pitucha, Tomasz M. Wróbel, and Dariusz Matosiuk. "Thermal and spectroscopic studies of 2,3,5-trisubstituted and 1,2,3,5-tetrasubstituted indoles as non-competitive antagonists of GluK1/GluK2 receptors." Journal of Thermal Analysis and Calorimetry 133, no. 2 (March 8, 2018): 935–44. http://dx.doi.org/10.1007/s10973-018-7146-6.

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18

Unno, Masaki, Masanobu Shinohara, Koichiro Takayama, Hideharu Tanaka, Kenta Teruya, Katsumi Doh-ura, Ryuichi Sakai, Makoto Sasaki, and Masao Ikeda-Saito. "Binding and Selectivity of the Marine Toxin Neodysiherbaine A and Its Synthetic Analogues to GluK1 and GluK2 Kainate Receptors." Journal of Molecular Biology 413, no. 3 (October 2011): 667–83. http://dx.doi.org/10.1016/j.jmb.2011.08.043.

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19

Andreou, Anna P., Philip R. Holland, Michele P. Lasalandra, and Peter J. Goadsby. "Modulation of nociceptive dural input to the trigeminocervical complex through GluK1 kainate receptors." PAIN 156, no. 3 (March 2015): 439–50. http://dx.doi.org/10.1097/01.j.pain.0000460325.25762.c0.

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20

Buldyrev, Ilya, Theresa Puthussery, and W. Rowland Taylor. "Synaptic pathways that shape the excitatory drive in an OFF retinal ganglion cell." Journal of Neurophysiology 107, no. 7 (April 1, 2012): 1795–807. http://dx.doi.org/10.1152/jn.00924.2011.

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Different types of retinal ganglion cells represent distinct spatiotemporal filters that respond selectively to specific features in the visual input. Much about the circuitry and synaptic mechanisms that underlie such specificity remains to be determined. This study examines how N-methyl-d-aspartate (NMDA) receptor signaling combines with other excitatory and inhibitory mechanisms to shape the output of small-field OFF brisk-sustained ganglion cells (OFF-BSGCs) in the rabbit retina. We used voltage clamp to separately resolve NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and inhibitory inputs elicited by stimulation of the receptive field center. Three converging circuits were identified. First is a direct glutamatergic input, arising from OFF cone bipolar cells (CBCs), which is mediated by synaptic NMDA and AMPA receptors. The NMDA input was saturated at 10% contrast, whereas the AMPA input increased monotonically up to 60% contrast. We propose that NMDA inputs selectively enhance sensitivity to low contrasts. The OFF bipolar cells, mediating this direct excitatory input, express dendritic kainate (KA) receptors, which are resistant to the nonselective AMPA/KA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide disodium salt (NBQX), but are suppressed by a GluK1- and GluK3-selective antagonist, ( S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-thiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione (UBP-310). The second circuit entails glycinergic crossover inhibition, arising from ON-CBCs and mediated by AII amacrine cells, which modulate glutamate release from the OFF-CBC terminals. The third circuit also comprises glycinergic crossover inhibition, which is driven by the ON pathway; however, this inhibition impinges directly on the OFF-BSGCs and is mediated by an unknown glycinergic amacrine cell that expresses AMPA but not KA receptors.
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21

Lv, Qian, Yong Liu, Dong Han, Jing Xu, Yan-Yan Zong, Yao Wang, and Guang-Yi Zhang. "Neuroprotection of GluK1 kainate receptor agonist ATPA against ischemic neuronal injury through inhibiting GluK2 kainate receptor–JNK3 pathway via GABAA receptors." Brain Research 1456 (May 2012): 1–13. http://dx.doi.org/10.1016/j.brainres.2012.03.050.

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22

Maiorov, S. A., V. P. Zinchenko, S. G. Gaidin, and A. M. Kosenkov. "Potential mechanism of GABA secretion in response to the activation of GluK1-containing kainate receptors." Neuroscience Research 171 (October 2021): 27–33. http://dx.doi.org/10.1016/j.neures.2021.03.009.

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23

Quijano Cardé, Natalia A., Erika E. Perez, Richard Feinn, Henry R. Kranzler, and Mariella De Biasi. "Antagonism of GluK1-containing kainate receptors reduces ethanol consumption by modulating ethanol reward and withdrawal." Neuropharmacology 199 (November 2021): 108783. http://dx.doi.org/10.1016/j.neuropharm.2021.108783.

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24

Han, Yan, Congzhou Wang, Jae Seon Park, and Li Niu. "Channel-Opening Kinetic Mechanism of Wild-Type GluK1 Kainate Receptors and a C-Terminal Mutant." Biochemistry 51, no. 3 (January 9, 2012): 761–68. http://dx.doi.org/10.1021/bi201446z.

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25

Irvine, Mark W., Blaise M. Costa, Daniel Dlaboga, Georgia R. Culley, Richard Hulse, Caroline L. Scholefield, Palmi Atlason, et al. "Piperazine-2,3-dicarboxylic Acid Derivatives as Dual Antagonists of NMDA and GluK1-Containing Kainate Receptors." Journal of Medicinal Chemistry 55, no. 1 (December 14, 2011): 327–41. http://dx.doi.org/10.1021/jm201230z.

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26

Zinchenko, Valery Petrovich, Artem Mikhailovich Kosenkov, Sergei Gennadevich Gaidin, Alexander Igorevich Sergeev, Ludmila Petrovna Dolgacheva, and Sultan Tuleukhanovich Tuleukhanov. "Properties of GABAergic Neurons Containing Calcium-Permeable Kainate and AMPA-Receptors." Life 11, no. 12 (November 27, 2021): 1309. http://dx.doi.org/10.3390/life11121309.

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Calcium-permeable kainate and AMPA receptors (CP-KARs and CP-AMPARs), as well as NMDARs, play a pivotal role in plasticity and in regulating neurotransmitter release. Here we visualized in the mature hippocampal neuroglial cultures the neurons expressing CP-AMPARs and CP-KARs. These neurons were visualized by a characteristic fast sustained [Ca2+]i increase in response to the agonist of these receptors, domoic acid (DoA), and a selective agonist of GluK1-containing KARs, ATPA. Neurons from both subpopulations are GABAergic. The subpopulation of neurons expressing CP-AMPARs includes a larger percentage of calbindin-positive neurons (39.4 ± 6.0%) than the subpopulation of neurons expressing CP-KARs (14.2 ± 7.5% of CB+ neurons). In addition, we have shown for the first time that NH4Cl-induced depolarization faster induces an [Ca2+]i elevation in GABAergic neurons expressing CP-KARs and CP-AMPARs than in most glutamatergic neurons. CP-AMPARs antagonist, NASPM, increased the amplitude of the DoA-induced Ca2+ response in GABAergic neurons expressing CP-KARs, indicating that neurons expressing CP-AMPARs innervate GABAergic neurons expressing CP-KARs. We assume that CP-KARs in inhibitory neurons are involved in the mechanism of outstripping GABA release upon hyperexcitation.
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Braga, Maria F. M., Vassiliki Aroniadou-Anderjaska, He Li, and Michael A. Rogawski. "Topiramate Reduces Excitability in the Basolateral Amygdala by Selectively Inhibiting GluK1 (GluR5) Kainate Receptors on Interneurons and Positively Modulating GABAA Receptors on Principal Neurons." Journal of Pharmacology and Experimental Therapeutics 330, no. 2 (May 5, 2009): 558–66. http://dx.doi.org/10.1124/jpet.109.153908.

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28

Copits, B. A., J. S. Robbins, S. Frausto, and G. T. Swanson. "Synaptic Targeting and Functional Modulation of GluK1 Kainate Receptors by the Auxiliary Neuropilin and Tolloid-Like (NETO) Proteins." Journal of Neuroscience 31, no. 20 (May 18, 2011): 7334–40. http://dx.doi.org/10.1523/jneurosci.0100-11.2011.

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29

Aroniadou-Anderjaska, V., V. I. Pidoplichko, T. H. Figueiredo, C. P. Almeida-Suhett, E. M. Prager, and M. F. M. Braga. "Presynaptic facilitation of glutamate release in the basolateral amygdala: A mechanism for the anxiogenic and seizurogenic function of GluK1 receptors." Neuroscience 221 (September 2012): 157–69. http://dx.doi.org/10.1016/j.neuroscience.2012.07.006.

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30

Herbrechter, Robin, Nadine Hube, Raoul Buchholz, and Andreas Reiner. "Splicing and editing of ionotropic glutamate receptors: a comprehensive analysis based on human RNA-Seq data." Cellular and Molecular Life Sciences 78, no. 14 (June 8, 2021): 5605–30. http://dx.doi.org/10.1007/s00018-021-03865-z.

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AbstractIonotropic glutamate receptors (iGluRs) play key roles for signaling in the central nervous system. Alternative splicing and RNA editing are well-known mechanisms to increase iGluR diversity and to provide context-dependent regulation. Earlier work on isoform identification has focused on the analysis of cloned transcripts, mostly from rodents. We here set out to obtain a systematic overview of iGluR splicing and editing in human brain based on RNA-Seq data. Using data from two large-scale transcriptome studies, we established a workflow for the de novo identification and quantification of alternative splice and editing events. We detected all canonical iGluR splice junctions, assessed the abundance of alternative events described in the literature, and identified new splice events in AMPA, kainate, delta, and NMDA receptor subunits. Notable events include an abundant transcript encoding the GluA4 amino-terminal domain, GluA4-ATD, a novel C-terminal GluD1 (delta receptor 1) isoform, GluD1-b, and potentially new GluK4 and GluN2C isoforms. C-terminal GluN1 splicing may be controlled by inclusion of a cassette exon, which shows preference for one of the two acceptor sites in the last exon. Moreover, we identified alternative untranslated regions (UTRs) and species-specific differences in splicing. In contrast, editing in exonic iGluR regions appears to be mostly limited to ten previously described sites, two of which result in silent amino acid changes. Coupling of proximal editing/editing and editing/splice events occurs to variable degree. Overall, this analysis provides the first inventory of alternative splicing and editing in human brain iGluRs and provides the impetus for further transcriptome-based and functional investigations.
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Miller, Justin Robert, Suzanne Neumueller, Clarissa Muere, Samantha Olesiak, Lawrence Pan, John D. Bukowy, Asem O. Daghistany, Matthew R. Hodges, and Hubert V. Forster. "Changes in glutamate receptor subunits within the medulla in goats after section of the carotid sinus nerves." Journal of Applied Physiology 116, no. 12 (June 15, 2014): 1531–42. http://dx.doi.org/10.1152/japplphysiol.00216.2014.

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The mechanisms which contribute to the time-dependent recovery of resting ventilation and the ventilatory CO2 chemoreflex after carotid body denervation (CBD) are poorly understood. Herein we tested the hypothesis that there are time-dependent changes in the expression of specific AMPA, NMDA, and/or neurokinin-1 (NK1R) receptors within respiratory-related brain stem nuclei acutely or chronically after CBD in adult goats. Brain stem tissues were collected acutely (5 days) or chronically (30 days) after sham or bilateral CBD, immunostained with antibodies targeting AMPA (GluA1 or GluA2), NMDA (GluN1), or NK-1 receptors, and optical density (OD) compared. Physiological measurement confirmed categorization of each group and showed ventilatory effects consistent with bilateral CBD (Miller et al. J Appl Physiol 115: 1088–1098, 2013). Acutely after CBD, GluA1 OD was unchanged or slightly increased, but GluA2 and GluN1 OD were reduced 15–30% within the nucleus tractus solitarius (NTS) and in other medullary respiratory nuclei. Chronically after CBD, GluA1 was reduced ( P < 0.05) within the caudal NTS and in other nuclei, but there was significant recovery of GluA2 and GluN1 OD. NK1 OD was not significantly different from control after CBD. We conclude that the initial decrease in GluA2 and GluN1 after CBD likely contributes to hypoventilation and the reduced CO2 chemoreflex. The partial recovery of ventilation and the CO2 chemoreflex after CBD parallel a time-dependent return of these receptors to near control levels but likely depend upon additional initiating and maintenance factors for neuroplasticity.
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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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33

Juuri, Juuso, Vernon R. J. Clarke, Sari E. Lauri, and Tomi Taira. "Kainate Receptor–Induced Ectopic Spiking of CA3 Pyramidal Neurons Initiates Network Bursts in Neonatal Hippocampus." Journal of Neurophysiology 104, no. 3 (September 2010): 1696–706. http://dx.doi.org/10.1152/jn.00840.2009.

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Kainate receptors (KARs) are expressed at high levels in the brain during early development and may be critical for the proper development of neuronal networks. Here we elucidated a physiological role of high-affinity KARs in developing hippocampal network by studying the effects of 25–100 nM kainate (KA) on intrinsic network activity in slice preparations. Whereas 100 nM KA resulted in hyperexcitability of the network and the disruption of natural activity patterns, ≤50 nM KA concentrations enhanced the initiation of network bursts yet preserved the characteristic patterns of endogenous activity. This was not dependent on changes in GABAergic transmission or on activation of GluK1 subunit containing KARs. However, the activation of high-affinity KARs increased glutamatergic drive by promoting spontaneous firing of CA3 pyramidal neurons without affecting action potential independent glutamate release. This was not because of changes in the intrinsic somatic properties of pyramidal neurons but seemed to reside in an electrically remote site, most probably in an axonal compartment. Although application of KAR agonists has mainly been used to study pathological type of network activities, this study provides a novel mechanism by which endogenous activity of KARs can modulate intrinsic activities of the emerging neuronal network in a physiologically relevant manner. The results support recent studies that KARs play a central role in the activity-dependent maturation of synaptic circuitries.
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He, Xue-Yan, Yan-Jun Li, Chakrapani Kalyanaraman, Li-Li Qiu, Chen Chen, Qi Xiao, Wen-Xue Liu, et al. "GluA1 signal peptide determines the spatial assembly of heteromeric AMPA receptors." Proceedings of the National Academy of Sciences 113, no. 38 (September 6, 2016): E5645—E5654. http://dx.doi.org/10.1073/pnas.1524358113.

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AMPA-type glutamate receptors (AMPARs) mediate fast excitatory neurotransmission and predominantly assemble as heterotetramers in the brain. Recently, the crystal structures of homotetrameric GluA2 demonstrated that AMPARs are assembled with two pairs of conformationally distinct subunits, in a dimer of dimers formation. However, the structure of heteromeric AMPARs remains unclear. Guided by the GluA2 structure, we performed cysteine mutant cross-linking experiments in full-length GluA1/A2, aiming to draw the heteromeric AMPAR architecture. We found that the amino-terminal domains determine the first level of heterodimer formation. When the dimers further assemble into tetramers, GluA1 and GluA2 subunits have preferred positions, possessing a 1–2–1–2 spatial assembly. By swapping the critical sequences, we surprisingly found that the spatial assembly pattern is controlled by the excisable signal peptides. Replacements with an unrelated GluK2 signal peptide demonstrated that GluA1 signal peptide plays a critical role in determining the spatial priority. Our study thus uncovers the spatial assembly of an important type of glutamate receptors in the brain and reveals a novel function of signal peptides.
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Bonini, Daniela, Cristina Mora, Paolo Tornese, Nathalie Sala, Alice Filippini, Luca La Via, Marco Milanese, et al. "Acute Footshock Stress Induces Time-Dependent Modifications of AMPA/NMDA Protein Expression and AMPA Phosphorylation." Neural Plasticity 2016 (2016): 1–10. http://dx.doi.org/10.1155/2016/7267865.

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Clinical studies on patients with stress-related neuropsychiatric disorders reported functional and morphological changes in brain areas where glutamatergic transmission is predominant, including frontal and prefrontal areas. In line with this evidence, several preclinical works suggest that glutamate receptors are targets of both rapid and long-lasting effects of stress. Here we found that acute footshock- (FS-) stress, although inducing no transcriptional and RNA editing alterations of ionotropic AMPA and NMDA glutamate receptor subunits, rapidly and transiently modulates their protein expression, phosphorylation, and localization at postsynaptic spines in prefrontal and frontal cortex. In total extract, FS-stress increased the phosphorylation levels of GluA1 AMPA subunit at Ser845immediately after stress and of GluA2 Ser8802 h after start of stress. At postsynaptic spines, stress induced a rapid decrease of GluA2 expression, together with an increase of its phosphorylation at Ser880, suggesting internalization of GluA2 AMPA containing receptors. GluN1 and GluN2A NMDA receptor subunits were found markedly upregulated in postsynaptic spines, 2 h after start of stress. These results suggest selected time-dependent changes in glutamatergic receptor subunits induced by acute stress, which may suggest early and transient enhancement of AMPA-mediated currents, followed by a transient activation of NMDA receptors.
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Otsu, Y., E. Darcq, K. Pietrajtis, F. Mátyás, E. Schwartz, T. Bessaih, S. Abi Gerges, et al. "Control of aversion by glycine-gated GluN1/GluN3A NMDA receptors in the adult medial habenula." Science 366, no. 6462 (October 10, 2019): 250–54. http://dx.doi.org/10.1126/science.aax1522.

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The unconventional N-methyl-d-aspartate (NMDA) receptor subunits GluN3A and GluN3B can, when associated with the other glycine-binding subunit GluN1, generate excitatory conductances purely activated by glycine. However, functional GluN1/GluN3 receptors have not been identified in native adult tissues. We discovered that GluN1/GluN3A receptors are operational in neurons of the mouse adult medial habenula (MHb), an epithalamic area controlling aversive physiological states. In the absence of glycinergic neuronal specializations in the MHb, glial cells tuned neuronal activity via GluN1/GluN3A receptors. Reducing GluN1/GluN3A receptor levels in the MHb prevented place-aversion conditioning. Our study extends the physiological and behavioral implications of glycine by demonstrating its control of negatively valued emotional associations via excitatory glycinergic NMDA receptors.
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Aksenova, S., A. Batova, A. Bugay, and E. Dushanov. "EFFECTS OF MODULATORS TO THE ACTIVATION OF NMDA RECEPTORS." Russian Journal of Biological Physics and Chemisrty 7, no. 3 (September 28, 2022): 418–22. http://dx.doi.org/10.29039/rusjbpc.2022.0537.

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In this paper, we have proposed a model approach for analyzing the properties of hippocampal neural networks with different types of NMDA receptors: GluN1/GluN2A, GluN1/GluN2B, GluN1/GluN2A/GluN2B. Molecular dynamics modeling of the activation of the ion channel of NMDA receptors modified by the action of allosteric modulators was carried out. The study of the network activity of neurons with a modified structure of NMDA receptors was carried out in models of neural networks in the CA1 and CA3 regions of the hippocampus. As a result of studying the properties of the neural network of the hippocampus with a modified structure of NMDA receptors, the electrophysiological characteristics of the neural network model were obtained depending on the structure of the ion channel of the NMDA receptor. Based on the analysis of changes in the conductivities of the ion channel and the binding of magnesium ions, differences in the amplitude of the theta and gamma frequency ranges in neural networks with different model structures of NMDA receptors were revealed. Analysis of the network activity of neurons with different types of NMDA revealed minor changes in the ion channel conductance and local potential depending on the subunits that make up the receptor and the type of modulator. Under the influence of Ro 25-6981 and ketamine for the diheteromeric model of the GluN1/GluN2A NMDA receptor, a decrease in the amplitude of the theta-frequency ranges and an increase in the gamma-frequency ranges were observed in comparison with the native forms of the receptor. For the GluN1/GluN2A/GluN2B trigger heteromer, there is an increase in theta frequency and a decrease in the gamma frequency compared to GluN1/GluN2B. In the absence of ketamine, for the GluN1/GluN2A and GluN1/GluN2A/GluN2B NMDA receptor models, an increase in the amplitude of theta-frequency and gamma-frequency ranges was observed compared to the native forms of the NMDA receptor.
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38

Bedoukian, Matthew A., Jennifer D. Whitesell, Erik J. Peterson, Colin M. Clay, and Kathryn M. Partin. "The Stargazin C Terminus Encodes an Intrinsic and Transferable Membrane Sorting Signal." Journal of Biological Chemistry 283, no. 3 (November 6, 2007): 1597–600. http://dx.doi.org/10.1074/jbc.m708141200.

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Activity-dependent plasticity of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors is regulated by their auxiliary subunit, stargazin. Association with stargazin enhances α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor surface expression and modifies the receptor's biophysical properties. Fusing the cytoplasmic C terminus of stargazin to the C-terminal domains of either GluR1 or the gonadotropin-releasing hormone receptor permits efficient trafficking from the endoplasmic reticulum and sorting to the basolateral membrane without altering other properties of either receptor.
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Fisher, Janet L., and Paul R. Housley. "Agonist binding to the GluK5 subunit is sufficient for functional surface expression of heteromeric GluK2/GluK5 kainate receptors." Cellular and Molecular Neurobiology 33, no. 8 (August 23, 2013): 1099–108. http://dx.doi.org/10.1007/s10571-013-9976-x.

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Delaney, Andrew J., Petra L. Sedlak, Elenora Autuori, John M. Power, and Pankaj Sah. "Synaptic NMDA receptors in basolateral amygdala principal neurons are triheteromeric proteins: physiological role of GluN2B subunits." Journal of Neurophysiology 109, no. 5 (March 1, 2013): 1391–402. http://dx.doi.org/10.1152/jn.00176.2012.

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N-methyl-d-aspartate (NMDA) receptors are heteromultimeric ion channels that contain an essential GluN1 subunit and two or more GluN2 (GluN2A–GluN2D) subunits. The biophysical properties and physiological roles of synaptic NMDA receptors are dependent on their subunit composition. In the basolateral amygdala (BLA), it has been suggested that the plasticity that underlies fear learning requires activation of heterodimeric receptors composed of GluN1/GluN2B subunits. In this study, we investigated the subunit composition of NMDA receptors present at synapses on principal neurons in the BLA. Purification of the synaptic fraction showed that both GluN2A and GluN2B subunits are present at synapses, and co-immunoprecipitation revealed the presence of receptors containing both GluN2A and GluN2B subunits. The kinetics of NMDA receptor-mediated synaptic currents and pharmacological blockade indicate that heterodimeric GluN1/GluN2B receptors are unlikely to be present at glutamatergic synapses on BLA principal neurons. Selective RNA interference-mediated knockdown of GluN2A subunits converted synaptic receptors to a GluN1/GluN2B phenotype, whereas knockdown of GluN2B subunits had no effect on the kinetics of the synaptically evoked NMDA current. Blockade of GluN1/GluN2B heterodimers with ifenprodil had no effect, but knockdown of GluN2B disrupted the induction of CaMKII-dependent long-term potentiation at these synapses. These results suggest that, on BLA principal neurons, GluN2B subunits are only present as GluN1/GluN2A/GluN2B heterotrimeric NMDA receptors. The GluN2B subunit has little impact on the kinetics of the receptor, but is essential for the recruitment of signaling molecules essential for synaptic plasticity.
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Sirrieh, Rita E., David M. MacLean, and Vasanthi Jayaraman. "A conserved structural mechanism of NMDA receptor inhibition: A comparison of ifenprodil and zinc." Journal of General Physiology 146, no. 2 (July 13, 2015): 173–81. http://dx.doi.org/10.1085/jgp.201511422.

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N-methyl-d-aspartate (NMDA) receptors, one of the three main types of ionotropic glutamate receptors (iGluRs), are involved in excitatory synaptic transmission, and their dysfunction is implicated in various neurological disorders. NMDA receptors, heterotetramers typically composed of GluN1 and GluN2 subunits, are the only members of the iGluR family that bind allosteric modulators at their amino-terminal domains (ATDs). We used luminescence resonance energy transfer to characterize the conformational changes the receptor undergoes upon binding ifenprodil, a synthetic compound that specifically inhibits activation of NMDA receptors containing GluN2B. We found that ifenprodil induced an overall closure of the GluN2B ATD without affecting conformation of the GluN1 ATD or the upper lobes of the ATDs, the same mechanism whereby zinc inhibits GluN2A. These data demonstrate that the conformational changes induced by zinc and ifenprodil represent a conserved mechanism of NMDA receptor inhibition. Additionally, we compared the structural mechanism of zinc inhibition of GluN1–GluN2A receptors to that of ifenprodil inhibition of GluN1–GluN2B. The similarities in the conformational changes induced by inhibitor binding suggest a conserved structural mechanism of inhibition independent of the binding site of the modulator.
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Stelljes, A., E. A. Bushong, M. E. Martone, P. W. Wiseman, K. L. Hood, M. Mayford, and M. H. Ellisman. "Study of Distribution and Transport Events of the GluR1 AMPA Receptor: Combination of Genetically Modified Receptors and Multi-Resolution Microscopy." Microscopy and Microanalysis 7, S2 (August 2001): 40–41. http://dx.doi.org/10.1017/s1431927600026271.

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The formation of memory and the process of learning are believed to be regulated, at least in part, by the expression, distribution, and redistribution of glutamate receptors. The expression of these receptors at synaptic sites has a major impact on the strength of synaptic connections, and the AMPA receptor subunit GluR1 appears to play a key role within this system. Increasing evidence suggests that previously silent synapses become activated through rapid AMPA receptor insertion upon appropriate stimulation, and thus the trafficking of this receptor subunit from cellular stores to the synapse is of prime interest.We are using a transgenic mouse expressing a GFP-tagged form of GluR1 (GluR1-GFP) in order to study the dynamic changes in GluR1 expression and distribution occurring during brain development and following induction of long-term potentiation (LTP). The fusion protein is transcribed under the control of the CaMKIIα promoter, which restricts the localization to forebrain neurons and is coupled to a tetrepressible system, thus allowing for the control of transcription with doxycycline. The anatomical distribution of GluR1-GFP on the light level is consistent with that of wild-type GluR1 (Fig. 1).We are combining molecular biology with quantitative 3D image analysis on the light and electron microscopic level. The highly fluorescent polar tracer Alexa Fluor 568 (Molecular Probes Inc.) is being used to fill GluR1-GFP expressing pyramidal neurons in tissue slices fixed with aldehydes
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Cummings, Kirstie A., and Gabriela K. Popescu. "Glycine-dependent activation of NMDA receptors." Journal of General Physiology 145, no. 6 (May 11, 2015): 513–27. http://dx.doi.org/10.1085/jgp.201411302.

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N-methyl-d-aspartate (NMDA) receptors are the only neurotransmitter receptors whose activation requires two distinct agonists. Heterotetramers of two GluN1 and two GluN2 subunits, NMDA receptors are broadly distributed in the central nervous system, where they mediate excitatory currents in response to synaptic glutamate release. Pore opening depends on the concurrent presence of glycine, which modulates the amplitude and time course of the glutamate-elicited response. Gating schemes for fully glutamate- and glycine-bound NMDA receptors have been described in sufficient detail to bridge the gap between microscopic and macroscopic receptor behaviors; for several receptor isoforms, these schemes include glutamate-binding steps. We examined currents recorded from cell-attached patches containing one GluN1/GluN2A receptor in the presence of several glycine-site agonists and used kinetic modeling of these data to develop reaction schemes that include explicit glycine-binding steps. Based on the ability to match a series of experimentally observed macroscopic behaviors, we propose a model for activation of the glutamate-bound NMDA receptor by glycine that predicts apparent negative agonist cooperativity and glycine-dependent desensitization in the absence of changes in microscopic binding or desensitization rate constants. These results complete the basic steps of an NMDA receptor reaction scheme for the GluN1/GluN2A isoform and prompt a reevaluation of how glycine controls NMDA receptor activation. We anticipate that our model will provide a useful quantitative instrument to further probe mechanisms and structure–function relationships of NMDA receptors and to better understand the physiological and pathological implications of endogenous fluctuations in extracellular glycine concentrations.
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Lee, Hey-Kyoung, Kogo Takamiya, Kaiwen He, Lihua Song, and Richard L. Huganir. "Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus." Journal of Neurophysiology 103, no. 1 (January 2010): 479–89. http://dx.doi.org/10.1152/jn.00835.2009.

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Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites (“double phosphomutants”), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the “double phosphomutants,” our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.
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Maki, Bruce A., and Gabriela K. Popescu. "Extracellular Ca2+ ions reduce NMDA receptor conductance and gating." Journal of General Physiology 144, no. 5 (October 27, 2014): 379–92. http://dx.doi.org/10.1085/jgp.201411244.

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Brief intracellular Ca2+ transients initiate signaling routines that direct cellular activities. Consequently, activation of Ca2+-permeable neurotransmitter-gated channels can both depolarize and initiate remodeling of the postsynaptic cell. In particular, the Ca2+ transient produced by NMDA receptors is essential to normal synaptic physiology, drives the development and plasticity of excitatory central synapses, and also mediates glutamate excitotoxicity. The amplitude and time course of the Ca2+ signal depends on the receptor’s conductance and gating kinetics; these properties are themselves influenced both directly and indirectly by fluctuations in the extracellular Ca2+ concentration. Here, we used electrophysiology and kinetic modeling to delineate the direct effects of extracellular Ca2+ on recombinant GluN1/GluN2A receptor conductance and gating. We report that, in addition to decreasing unitary conductance, Ca2+ also decreased channel open probability primarily by lengthening closed-channel periods. Using one-channel current recordings, we derive a kinetic model for GluN1/GluN2A receptors in physiological Ca2+ concentrations that accurately describes macroscopic channel behaviors. This model represents a practical instrument to probe the mechanisms that control the Ca2+ transients produced by NMDA receptors during both normal and aberrant synaptic signaling.
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Elmasri, Marwa, James S. Lotti, Wajeeha Aziz, Oliver G. Steele, Eirini Karachaliou, Kenji Sakimura, Kasper B. Hansen, and Andrew C. Penn. "Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification." Brain Sciences 12, no. 6 (June 15, 2022): 789. http://dx.doi.org/10.3390/brainsci12060789.

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GRIN2B mutations are rare but often associated with patients having severe neurodevelopmental disorders with varying range of symptoms such as intellectual disability, developmental delay and epilepsy. Patient symptoms likely arise from mutations disturbing the role that the encoded NMDA receptor subunit, GluN2B, plays at neuronal connections in the developing nervous system. In this study, we investigated the cell-autonomous effects of putative gain- (GoF) and loss-of-function (LoF) missense GRIN2B mutations on excitatory synapses onto CA1 pyramidal neurons in organotypic hippocampal slices. In the absence of both native GluN2A and GluN2B subunits, functional incorporation into synaptic NMDA receptors was attenuated for GoF mutants, or almost eliminated for LoF GluN2B mutants. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA-EPSCs) from synaptic GoF GluN1/2B receptors had prolonged decays consistent with their functional classification. Nonetheless, in the presence of native GluN2A, molecular replacement of native GluN2B with GoF and LoF GluN2B mutants all led to similar functional incorporation into synaptic receptors, more rapidly decaying NMDA-EPSCs and greater inhibition by TCN-201, a selective antagonist for GluN2A-containing NMDA receptors. Mechanistic insight was gained from experiments in HEK293T cells, which revealed that GluN2B GoF mutants slowed deactivation in diheteromeric GluN1/2B, but not triheteromeric GluN1/2A/2B receptors. We also show that a disease-associated missense mutation, which severely affects surface expression, causes opposing effects on NMDA-EPSC decay and charge transfer when introduced into GluN2A or GluN2B. Finally, we show that having a single null Grin2b allele has only a modest effect on NMDA-EPSC decay kinetics. Our results demonstrate that functional incorporation of GoF and LoF GluN2B mutants into synaptic receptors and the effects on EPSC decay times are highly dependent on the presence of triheteromeric GluN1/2A/2B NMDA receptors, thereby influencing the functional classification of NMDA receptor variants as GoF or LoF mutations. These findings highlight the complexity of interpreting effects of disease-causing NMDA receptor missense mutations in the context of neuronal function.
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Armstrong, Scott P., Paul J. Banks, Thomas J. W. McKitrick, Catharine H. Geldart, Christopher J. Edge, Rohan Babla, Constantinos Simillis, Nicholas P. Franks, and Robert Dickinson. "Identification of Two Mutations (F758W and F758Y) in the N -methyl-D-aspartate Receptor Glycine-binding Site that Selectively Prevent Competitive Inhibition by Xenon without Affecting Glycine Binding." Anesthesiology 117, no. 1 (July 1, 2012): 38–47. http://dx.doi.org/10.1097/aln.0b013e31825ada2e.

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Background Xenon is a general anesthetic with neuroprotective properties. Xenon inhibition at the glycine-binding site of the N-Methyl-D-aspartate (NMDA) receptor mediates xenon neuroprotection against ischemic injury in vitro. Here we identify specific amino acids important for xenon binding to the NMDA receptor, with the aim of finding silent mutations that eliminate xenon binding but leave normal receptor function intact. Methods Site-directed mutagenesis was used to mutate specific amino-acids in the GluN1 subunit of rat NMDA receptors. Mutant GluN1/GluN2A receptors were expressed in HEK 293 cells and were assessed functionally using patch-clamp electrophysiology. The responses of the mutant receptors to glycine and anesthetics were determined. Results Mutation of phenylalanine 758 to an aromatic tryptophan or tyrosine left glycine affinity unchanged, but eliminated xenon binding without affecting the binding of sevoflurane or isoflurane. Conclusions These findings confirm xenon binds to the glycine site of the GluN1 subunit of the NMDA receptor and indicate that interactions between xenon and the aromatic ring of the phenylalanine 758 residue are important for xenon binding. Our most important finding is that we have identified two mutations, F758W and F758Y, that eliminate xenon binding to the NMDA receptor glycine site without changing the glycine affinity of the receptor or the binding of volatile anesthetics. The identification of these selective mutations will allow knock-in animals to be used to dissect the mechanism(s) of xenon's neuroprotective and anesthetic properties in vivo.
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Tarusawa, Etsuko, Kaori Akashi, Kenji Sakimura, Elek Molnar, Yugo Fukazawa, Yumiko Yoshimura, and Ryuichi Shigemoto. "Immunohistochemical localization of kainate receptors, GluK2/3 (GluR6/7) and GluK5 (KA2), in the mouse hippocampus." Neuroscience Research 68 (January 2010): e230-e231. http://dx.doi.org/10.1016/j.neures.2010.07.1018.

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49

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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Lind, Genevieve E., Tung-Chung Mou, Lucia Tamborini, Martin G. Pomper, Carlo De Micheli, Paola Conti, Andrea Pinto, and Kasper B. Hansen. "Structural basis of subunit selectivity for competitive NMDA receptor antagonists with preference for GluN2A over GluN2B subunits." Proceedings of the National Academy of Sciences 114, no. 33 (July 31, 2017): E6942—E6951. http://dx.doi.org/10.1073/pnas.1707752114.

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Abstract:
NMDA-type glutamate receptors are ligand-gated ion channels that contribute to excitatory neurotransmission in the central nervous system (CNS). Most NMDA receptors comprise two glycine-binding GluN1 and two glutamate-binding GluN2 subunits (GluN2A–D). We describe highly potent (S)-5-[(R)-2-amino-2-carboxyethyl]-4,5-dihydro-1H-pyrazole-3-carboxylic acid (ACEPC) competitive GluN2 antagonists, of which ST3 has a binding affinity of 52 nM at GluN1/2A and 782 nM at GluN1/2B receptors. This 15-fold preference of ST3 for GluN1/2A over GluN1/2B is improved compared with NVP-AAM077, a widely used GluN2A-selective antagonist, which we show has 11-fold preference for GluN1/2A over GluN1/2B. Crystal structures of the GluN1/2A agonist binding domain (ABD) heterodimer with bound ACEPC antagonists reveal a binding mode in which the ligands occupy a cavity that extends toward the subunit interface between GluN1 and GluN2A ABDs. Mutational analyses show that the GluN2A preference of ST3 is primarily mediated by four nonconserved residues that are not directly contacting the ligand, but positioned within 12 Å of the glutamate binding site. Two of these residues influence the cavity occupied by ST3 in a manner that results in favorable binding to GluN2A, but occludes binding to GluN2B. Thus, we reveal opportunities for the design of subunit-selective competitive NMDA receptor antagonists by identifying a cavity for ligand binding in which variations exist between GluN2A and GluN2B subunits. This structural insight suggests that subunit selectivity of glutamate-site antagonists can be mediated by mechanisms in addition to direct contributions of contact residues to binding affinity.
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