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The Journal of Neuroscience : the... Jan 2000AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have... (Comparative Study)
Comparative Study
AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have been shown in various models to be more susceptible to AMPA receptor-mediated injury than other spinal neurons. It has been hypothesized that this selective vulnerability of motoneurons is caused by the expression of highly Ca(2+)-permeable AMPA receptors and a complete or relative lack of the AMPA receptor subunit Glu receptor 2 (GluR2). The aim of this study was to quantify the relative Ca(2+) permeability of AMPA receptors and the fractional expression of GluR2 in motoneurons by combining whole-cell patch-clamp electrophysiology and single-cell RT-PCR and to compare these properties with those of dorsal horn neurons. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. As in previous studies, motoneurons were significantly more vulnerable to AMPA and kainate than dorsal horn neurons. However, all motoneurons expressed GluR2 mRNA ( approximately 40% of total AMPA receptor subunit mRNA), and their AMPA receptors had intermediate whole-cell relative Ca(2+) permeability (P(Ca(2+))/P(Cs(+)) approximately 0. 4). AMPA receptor P(Ca(2+))/P(Cs(+)) and the relative abundance of GluR2 varied more widely in dorsal horn neurons than in motoneurons, but the mean values did not differ significantly between the two cell populations. GluR2 was virtually completely edited at the Q/R site both in motoneurons and dorsal horn neurons. These results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca(2+) permeability of AMPA receptors.
Topics: Amyotrophic Lateral Sclerosis; Animals; Calcium; Cell Survival; Cells, Cultured; Excitatory Amino Acid Agonists; Gene Expression; Kainic Acid; Motor Neurons; Nerve Degeneration; Neurotoxins; Patch-Clamp Techniques; Posterior Horn Cells; RNA, Messenger; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Reverse Transcriptase Polymerase Chain Reaction; Spinal Cord; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 10627588
DOI: 10.1523/JNEUROSCI.20-01-00123.2000 -
International Journal of Molecular... Jun 2023The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trione-had been developed and...
The synthetic approaches to three new AMPA receptor modulators-derivatives of 1,11-dimethyl-3,6,9-triazatricyclo[7.3.1.1]tetradecane-4,8,12-trione-had been developed and all steps of synthesis were optimized. The structures of the compounds contain tricyclic cage and indane fragments necessary for binding with the target receptor. Their physiological activity was studied by radioligand-receptor binding analysis using [H]PAM-43 as a reference ligand, which is a highly potent positive allosteric modulator of AMPA receptors. The results of radioligand-binding studies indicated the high potency of two synthesized compounds to bind with the same targets as positive allosteric modulator PAM-43 (at least on AMPA receptors). We suggest that the Glu-dependent specific binding site of [H]PAM-43 or the receptor containing this site may be one of the targets of the new compounds. We also suggest that enhanced radioligand binding may indicate the existence of synergistic effects of compounds and with respect to PAM-43 binding to the targets. At the same time, these compounds may not compete directly with PAM-43 for its specific binding sites but bind to other specific sites of this biotarget, changing its conformation and thereby causing a synergistic effect of cooperative interaction. It can be expected that the newly synthesized compounds will also have pronounced effects on the glutamatergic system of the mammalian brain.
Topics: Animals; Receptors, AMPA; Allosteric Regulation; Protein Binding; Binding Sites; Ligands; Allosteric Site; Mammals
PubMed: 37373440
DOI: 10.3390/ijms241210293 -
The Journal of Neuroscience : the... Aug 2001Most AMPA-type glutamate receptors (GluRs) exhibit rapid and virtually complete desensitization when activated by glutamate, and at some central synapses it is largely...
Most AMPA-type glutamate receptors (GluRs) exhibit rapid and virtually complete desensitization when activated by glutamate, and at some central synapses it is largely desensitization that determines the decay of EPSCs. However, the mechanisms underlying the conformation change that results in desensitization are not fully understood. AMPA receptor subunits that contain a single amino acid substitution have been shown to form homomeric channels that show markedly reduced desensitization. We show here that the coexpression of wild-type GluR1 with one such mutant, GluR1(L497Y), results in heteromeric channels that show desensitization behavior that is intermediate between wild-type and mutant homomers. The relative amplitudes of the multiple exponential components present in the decay of glutamate-evoked currents depended on the relative abundance of wild-type and mutant subunits and were described by the combinatorial distribution of the two types of subunits into tetrameric, but not pentameric, assemblies. Our results are consistent with recent structural data suggesting that AMPA receptors are tetrameric assemblies composed of two dimers.
Topics: Amino Acid Substitution; Animals; Cell Line; Cells, Cultured; Dimerization; Excitatory Postsynaptic Potentials; Gene Expression; Glutamic Acid; Kidney; Models, Neurological; Mutagenesis, Site-Directed; Neurons; Patch-Clamp Techniques; Phenotype; Protein Binding; Protein Subunits; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, AMPA; Transfection
PubMed: 11466429
DOI: 10.1523/JNEUROSCI.21-15-05574.2001 -
Seminars in Cell & Developmental Biology Mar 2014AMPA receptors are the main excitatory neurotransmitter receptor in the brain, and hence regulating the number or properties of synaptic AMPA receptors brings about... (Review)
Review
AMPA receptors are the main excitatory neurotransmitter receptor in the brain, and hence regulating the number or properties of synaptic AMPA receptors brings about critical changes in synaptic transmission. Synaptic plasticity is thought to underlie learning and memory, and can be brought about by decreasing or increasing the number of AMPA receptors localised to synaptic sites by precisely regulating AMPA receptor trafficking. AMPA receptors are tetrameric assemblies of subunits GluA1-4, and the vast majority are GluA1/2 and GluA2/3 heteromers. The inclusion of GluA2 subunit is critical because it renders the AMPA receptor channel impermeable to Ca(2+) ions. The vast majority of synaptic AMPA receptors in the brain contain GluA2, but relatively recent discoveries indicate that an increasing number of specific forms of synaptic plasticity involve not only an alteration of the number of synaptic AMPA receptors, but also changes to their GluA2 content. The resulting change in AMPA receptor Ca(2+) permeability clearly has profound consequences for synaptic transmission and intracellular signalling events. The subunit-specific trafficking mechanisms that cause such changes represent an emerging field of research with implications for an increasing number of physiological or pathological situations, and are the topic of this review.
Topics: Animals; Calcium; Calcium Signaling; Cell Membrane Permeability; Endosomes; Gene Expression Regulation; Humans; Protein Subunits; Protein Transport; Receptors, AMPA; Synapses
PubMed: 24342448
DOI: 10.1016/j.semcdb.2013.12.002 -
The Journal of Neuroscience : the... Jan 2006Craving and relapse are core symptoms of drug addiction and alcoholism. It is suggested that, after chronic drug consumption, long-lasting neuroplastic changes within...
Craving and relapse are core symptoms of drug addiction and alcoholism. It is suggested that, after chronic drug consumption, long-lasting neuroplastic changes within the glutamatergic system are important determinants of addictive behavior. Here, we show that the AMPA type glutamate receptor plays a crucial role in alcohol craving and relapse. We observed, in two animal models of alcohol craving and relapse, that the AMPA antagonist GYKI 52466 [1-(4-aminophenyl)-4-methyl-7, 8-methylenedioxy-5H-2, 3-benzodiazepine] dose-dependently reduced cue-induced reinstatement of alcohol-seeking behavior and the alcohol deprivation effect. The involvement of the AMPA receptor in these phenomena was further studied using mice deficient for the GluR-C AMPA subunit [GluR-C knock-out (KO)]. GluR-C KOs displayed a blunted, cue-induced reinstatement response and alcohol deprivation effect, when compared with wild-type controls; however, no differences between genotypes could be observed regarding ethanol self-administration under operant or home cage drinking conditions. These results imply a role for GluR-C in alcohol relapse, although this phenotype could also be attributable to a reduction in the total number of AMPA receptors in specific brain areas. In conclusion, AMPA receptors seem to be involved in the neuroplastic changes underlying alcohol seeking behavior and relapse. Thus, AMPA receptors represent a novel therapeutic target in preventing relapse.
Topics: Alcoholism; Animals; Benzodiazepines; Conditioning, Operant; Cues; Ethanol; Excitatory Amino Acid Antagonists; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Protein Subunits; Random Allocation; Rats; Rats, Wistar; Receptors, AMPA; Recurrence; Species Specificity; Substance Withdrawal Syndrome
PubMed: 16436610
DOI: 10.1523/JNEUROSCI.4237-05.2006 -
Journal of Neurophysiology Jul 2001The actions of the trivalent cation Gd(3+) on whole cell AMPA receptor-mediated currents were studied in isolated hippocampal neurons, in nucleated or outside-out...
The actions of the trivalent cation Gd(3+) on whole cell AMPA receptor-mediated currents were studied in isolated hippocampal neurons, in nucleated or outside-out patches taken from cultured hippocampal neurons, and on miniature excitatory postsynaptic currents (mEPSCs) recorded in cultured hippocampal neurons. Glutamate, AMPA, or kainate was employed to activate AMPA receptors. Applications of relatively low concentrations of Gd(3+) (0.1-10 microM) substantially enhanced steady-state whole cell glutamate and kainate-evoked currents without altering peak currents, suggesting that desensitization was reduced. However, higher concentrations (>30 microM) depressed steady-state currents, indicating an underlying inhibition of channel activity. Lower concentrations of Gd(3+) also increased the potency of peak glutamate-evoked currents without altering that of steady-state currents. An ultrafast perfusion system and nucleated patches were then used to better resolve peak glutamate-evoked currents. Low concentrations of Gd(3+) reduced peak currents, enhanced steady-state currents, and slowed the onset of desensitization, providing further evidence that this cation reduces desensitization. In the presence of cyclothiazide, a compound that blocks desensitization, a low concentration Gd(3+) inhibited both peak and steady-state currents, indicating that Gd(3+) both reduces desensitization and inhibits these currents. Gd(3+) reduced the probability of channel opening at the peak of the currents but did not alter the single channel conductance calculated using nonstationary variance analysis. Recovery from desensitization was enhanced, and glutamate-evoked current activation and deactivation were slowed by Gd(3+). The Gd(3+)-induced reduction in desensitization did not require the presence of the GluR2 subunit as this effect was seen in hippocampal neurons from GluR2 null-mutant mice. Gd(3+) reduced the time course of decay of mEPSCs perhaps as a consequence of its slowing of AMPA receptor deactivation although an increase in the frequency of mEPSCs also suggested enhanced presynaptic release of transmitter. These results demonstrate that Gd(3+) potently reduces AMPA receptor desensitization and mimics a number of the properties of the positive modulators of AMPA receptor desensitization such as cyclothiazide.
Topics: Animals; Drug Synergism; Excitatory Postsynaptic Potentials; Gadolinium; Glutamic Acid; Hippocampus; Ion Channel Gating; Membrane Potentials; Mice; Mice, Mutant Strains; Neurons; Patch-Clamp Techniques; Rats; Rats, Wistar; Receptors, AMPA
PubMed: 11431499
DOI: 10.1152/jn.2001.86.1.173 -
Nature Communications Jun 2011Ionotropic glutamate receptors (iGluRs) mediate fast excitatory synaptic transmission in the central nervous system. Upon agonist binding, an iGluR opens to allow the...
Ionotropic glutamate receptors (iGluRs) mediate fast excitatory synaptic transmission in the central nervous system. Upon agonist binding, an iGluR opens to allow the flow of cations and subsequently enters into a desensitized state. It remains unclear how agonist binding to the ligand-binding domain (LBD) is transmitted to the transmembrane domain (TMD) for channel activation and desensitization. Here we report molecular dynamics simulations of an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-subtype iGluR in explicit water and membrane. Channel opening and closing were observed in simulations of the activation and desensitization processes, respectively. The motions of the LBD-TMD linkers along the central axis of the receptor and in the lateral plane contributed cooperatively to channel opening and closing. The detailed mechanism of channel activation and desensitization suggested by the simulations here is consistent with existing data and may serve as a guide for new experiments and for the design of pharmacological agents.
Topics: Amino Acid Sequence; Central Nervous System; Crystallography; Electrophysiology; Humans; Ion Channel Gating; Ligands; Models, Molecular; Molecular Dynamics Simulation; Molecular Sequence Data; Protein Conformation; Receptors, AMPA; Synaptic Transmission
PubMed: 21673675
DOI: 10.1038/ncomms1362 -
Proceedings of the National Academy of... Apr 2019Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors...
Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific protein phosphatase that regulates a variety of synaptic proteins, including NMDA receptors (NAMDRs). To better understand STEP's effect on other receptors, we used mass spectrometry to identify the STEP interactome. We identified a number of known interactors, but also ones including the GluA2 subunit of AMPA receptors (AMPARs). We show that STEP binds to the C termini of GluA2 and GluA3 as well as endogenous AMPARs in hippocampus. The synaptic expression of GluA2 and GluA3 is increased in STEP-KO mouse brain, and STEP knockdown in hippocampal slices increases AMPAR-mediated synaptic currents. Interestingly, STEP overexpression reduces the synaptic expression and synaptic currents of both AMPARs and NMDARs. Furthermore, STEP regulation of synaptic AMPARs is mediated by lysosomal degradation. Thus, we report a comprehensive list of STEP binding partners, including AMPARs, and reveal a central role for STEP in differentially organizing synaptic AMPARs and NMDARs.
Topics: Animals; Chromatography, Liquid; Lysosomes; Mice; Phosphorylation; Protein Binding; Protein Tyrosine Phosphatases; Receptors, AMPA; Synapses; Tandem Mass Spectrometry
PubMed: 30936304
DOI: 10.1073/pnas.1900878116 -
International Journal of Molecular... May 2019Glia form a central component of the nervous system whose varied activities sustain an environment that is optimised for healthy development and neuronal function.... (Review)
Review
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.
Topics: Animals; Gene Expression Regulation; Glutamic Acid; Humans; Nervous System Diseases; Neuroglia; Receptors, AMPA; Synaptic Transmission
PubMed: 31108947
DOI: 10.3390/ijms20102450 -
Neuropsychopharmacology : Official... Nov 2022Long-lasting fear-related disorders depend on the excessive retention of traumatic fear memory. We previously showed that the palmitoylation-dependent removal of...
Long-lasting fear-related disorders depend on the excessive retention of traumatic fear memory. We previously showed that the palmitoylation-dependent removal of synaptic α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors prevents hyperexcitation-based epileptic seizures and that AMPA receptor palmitoylation maintains neural network stability. In this study, AMPA receptor subunit GluA1 C-terminal palmitoylation-deficient (GluA1C811S) mice were subjected to comprehensive behavioral battery tests to further examine whether the mutation causes other neuropsychiatric disease-like symptoms. The behavioral analyses revealed that palmitoylation-deficiency in GluA1 is responsible for characteristic prolonged contextual fear memory formation, whereas GluA1C811S mice showed no impairment of anxiety-like behaviors at the basal state. In addition, fear generalization gradually increased in these mutant mice without affecting their cued fear. Furthermore, fear extinction training by repeated exposure of mice to conditioned stimuli had little effect on GluA1C811S mice, which is in line with augmentation of synaptic transmission in pyramidal neurons in the basolateral amygdala. In contrast, locomotion, sociability, depression-related behaviors, and spatial learning and memory were unaffected by the GluA1 non-palmitoylation mutation. These results indicate that impairment of AMPA receptor palmitoylation specifically causes posttraumatic stress disorder (PTSD)-like symptoms.
Topics: Animals; Extinction, Psychological; Fear; Mice; Propionates; Receptors, AMPA; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 35618841
DOI: 10.1038/s41386-022-01347-9