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Cell Adhesion & Migration 2008
Review
Topics: Animals; Cell Membrane; Dendritic Spines; Protein Transport; Receptors, AMPA; Signal Transduction; Spine
PubMed: 19262155
DOI: 10.4161/cam.2.4.6510 -
The Journal of Neuroscience : the... Jan 2010Glutamate is a major excitatory neurotransmitter in the vertebrate brain. AMPA-type glutamate receptors mediate fast excitatory transmission. AMPA receptors assemble...
Glutamate is a major excitatory neurotransmitter in the vertebrate brain. AMPA-type glutamate receptors mediate fast excitatory transmission. AMPA receptors assemble with transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits and function as native ion channels. However, the assembly and stoichiometry of AMPA receptor and TARP complexes remain unclear. Here, we developed a novel strategy to determine the assembly and stoichiometry of this protein complex and found that functional AMPA receptors indeed assembled as a tetramer in a dimer-of-dimers structure. Furthermore, we found that the AMPA receptor auxiliary subunit, TARP, had a variable stoichiometry (1-4 TARP units) on AMPA receptors and that 1 TARP unit was sufficient to modulate AMPA receptor activity. In neurons, TARP had fixed and minimum stoichiometry on AMPA receptors. This fundamental composition of the AMPA receptor/TARP complex is important for the elucidation of the molecular machinery that underlies synaptic transmission.
Topics: Animals; Calcium Channels; Green Fluorescent Proteins; Hemagglutinins; Larva; Membrane Potentials; Models, Molecular; Mutation; Nuclear Proteins; Oocytes; Patch-Clamp Techniques; Protein Conformation; Receptors, AMPA; Receptors, Glutamate; Stochastic Processes; Transcription, Genetic; Xenopus; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
PubMed: 20089915
DOI: 10.1523/JNEUROSCI.3909-09.2010 -
Neuron Jun 2007The AMPA receptor (AMPAR) GluR2 subunit dictates the critical biophysical properties of the receptor, strongly influences receptor assembly and trafficking, and plays... (Review)
Review
The AMPA receptor (AMPAR) GluR2 subunit dictates the critical biophysical properties of the receptor, strongly influences receptor assembly and trafficking, and plays pivotal roles in a number of forms of long-term synaptic plasticity. Most neuronal AMPARs contain this critical subunit; however, in certain restricted neuronal populations and under certain physiological or pathological conditions, AMPARs that lack this subunit are expressed. There is a current surge of interest in such GluR2-lacking Ca2+-permeable AMPARs in how they affect the regulation of synaptic transmission. Here, we bring together recent data highlighting the novel and important roles of GluR2 in synaptic function and plasticity.
Topics: Animals; Calcium; Models, Biological; Neuronal Plasticity; Receptors, AMPA; Synapses
PubMed: 17582328
DOI: 10.1016/j.neuron.2007.06.001 -
Life Science Alliance Apr 2022In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of...
In motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients, the RNA editing at the glutamine/arginine site of the GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is defective or incomplete. As a result, AMPA receptors containing the abnormally expressed, unedited isoform of GluA2 are highly Ca-permeable, and are responsible for mediating abnormal Ca influx, thereby triggering motor neuron degeneration and cell death. Thus, blocking the AMPA receptor-mediated, abnormal Ca influx is a potential therapeutic strategy for treatment of sporadic ALS. Here, we report a study of the efficacy and safety of two RNA aptamers targeting AMPA receptors on the ALS phenotype of AR2 mice. A 12-wk continuous, intracerebroventricular infusion of aptamers to AR2 mice reduced the progression of motor dysfunction, normalized TDP-43 mislocalization, and prevented death of motor neurons. Our results demonstrate that the use of AMPA receptor aptamers as a novel class of AMPA receptor antagonists is a promising strategy for developing an ALS treatment approach.
Topics: Amyotrophic Lateral Sclerosis; Animals; Aptamers, Nucleotide; Disease Models, Animal; Drug Delivery Systems; Male; Mice; Motor Neurons; RNA Editing; Receptors, AMPA
PubMed: 35022247
DOI: 10.26508/lsa.202101193 -
Acta Neurologica Scandinavica.... 2013Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of non-conventional mechanisms may... (Review)
Review
Epileptic seizures occur as a result of episodic abnormal synchronous discharges in cerebral neuronal networks. Although a variety of non-conventional mechanisms may play a role in epileptic synchronization, cascading excitation within networks of synaptically connected excitatory glutamatergic neurons is a classical mechanism. As is the case throughout the central nervous system, fast synaptic excitation within and between brain regions relevant to epilepsy is mediated predominantly by AMPA receptors. By inhibiting glutamate-mediated excitation, AMPA receptor antagonists markedly reduce or abolish epileptiform activity in in vitro preparations and confer seizure protection in a broad range of animal seizure models. NMDA receptors may also contribute to epileptiform activity, but NMDA receptor blockade is not sufficient to eliminate epileptiform discharges. AMPA receptors move into and out of the synapse in a dynamic fashion in forms of synaptic plasticity, underlying learning and memory. Often, the trigger for these dynamic movements is the activation of NMDA receptors. While NMDA receptor antagonists inhibit these forms of synaptic plasticity, AMPA receptor antagonists do not impair synaptic plasticity and do not inhibit memory formation or retrieval. The demonstrated clinical efficacy of perampanel, a high-potency, orally active non-competitive AMPA receptor antagonist, supports the concept that AMPA receptors are critical to epileptic synchronization and the generation and spread of epileptic discharges in human epilepsy.
Topics: Animals; Anticonvulsants; Brain; Epilepsy; Excitatory Amino Acid Antagonists; Humans; Models, Biological; Receptors, AMPA; Synaptic Transmission
PubMed: 23480151
DOI: 10.1111/ane.12099 -
The Journal of Biological Chemistry Apr 2011AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple...
AMPA receptors mediate fast excitatory transmission in the brain. Neuronal AMPA receptors comprise GluA pore-forming principal subunits and can associate with multiple modulatory components, including transmembrane AMPA receptor regulatory proteins (TARPs) and CNIHs (cornichons). AMPA receptor potentiators and non-competitive antagonists represent potential targets for a variety of neuropsychiatric disorders. Previous studies showed that the AMPA receptor antagonist GYKI-53655 displaces binding of a potentiator from brain receptors but not from recombinant GluA subunits. Here, we asked whether AMPA receptor modulatory subunits might resolve this discrepancy. We find that the cerebellar TARP, stargazin (γ-2), enhances the binding affinity of the AMPA receptor potentiator [(3)H]-LY450295 and confers sensitivity to displacement by non-competitive antagonists. In cerebellar membranes from stargazer mice, [(3)H]-LY450295 binding is reduced and relatively resistant to displacement by non-competitive antagonists. Coexpression of AMPA receptors with CNIH-2, which is expressed in the hippocampus and at low levels in the cerebellar Purkinje neurons, confers partial sensitivity of [(3)H]-LY450295 potentiator binding to displacement by non-competitive antagonists. Autoradiography of [(3)H]-LY450295 binding to stargazer and γ-8-deficient mouse brain sections, demonstrates that TARPs regulate the pharmacology of allosteric AMPA potentiators and antagonists in the cerebellum and hippocampus, respectively. These studies demonstrate that accessory proteins define AMPA receptor pharmacology by functionally linking allosteric AMPA receptor potentiator and antagonist sites.
Topics: Allosteric Regulation; Animals; Benzodiazepines; Calcium Channels; Cell Membrane; Egg Proteins; Excitatory Amino Acid Antagonists; HEK293 Cells; Humans; Membrane Proteins; Mice; Purkinje Cells; Receptors, AMPA
PubMed: 21343286
DOI: 10.1074/jbc.M110.212522 -
The Journal of Physiology Sep 2011In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA- and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit... (Review)
Review
In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA- and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit proteins that determine their biophysical properties and trafficking behaviour. Therefore, determining the function of these subunits and receptor subunit composition is essential for understanding the physiological properties of synaptic transmission. Here, we discuss and evaluate various genetic approaches that have been used to study AMPA and NMDA receptor subunits. These approaches have demonstrated that the GluA1 AMPA receptor subunit is required for activity-dependent trafficking and contributes to basal synaptic transmission, while the GluA2 subunit regulates Ca(2+) permeability, homeostasis and trafficking to the synapse under basal conditions. In contrast, the GluN2A and GluN2B NMDA receptor subunits regulate synaptic AMPA receptor content, both during synaptic development and plasticity. Ongoing research in this field is focusing on the molecular interactions and mechanisms that control these functions. To accomplish this, molecular replacement techniques are being used, where native subunits are replaced with receptors containing targeted mutations. In this review, we discuss a single-cell molecular replacement approach which should arguably advance our physiological understanding of ionotropic glutamate receptor subunits, but is generally applicable to study of any neuronal protein.
Topics: Brain; Glutamic Acid; Protein Subunits; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 21768264
DOI: 10.1113/jphysiol.2011.213033 -
Current Opinion in Pharmacology Feb 2015Positive allosteric modulators of ionotropic glutamate receptors have emerged as a target for treating cognitive impairment and neurodegeneration, but also mental... (Review)
Review
Positive allosteric modulators of ionotropic glutamate receptors have emerged as a target for treating cognitive impairment and neurodegeneration, but also mental illnesses such as major depressive disorder. The possibility of creating a new class of pharmaceutical agent to treat refractive mental health issues has compelled researchers to redouble their efforts to develop a safe, effective treatment for memory and cognition impairments. Coupled with the more robust research methodologies that have emerged, including more sophisticated high-throughput-screens, higher resolution structural biology techniques, and more focused assessment on pharmacokinetics, the development of positive modulators of AMPA receptors holds great promise. We describe recent approaches that improve our understanding of the basic physiology underlying memory and cognition, and their application toward promoting human health.
Topics: Allosteric Regulation; Animals; Cognition; Cognition Disorders; Depressive Disorder, Major; Drug Design; High-Throughput Screening Assays; Humans; Memory Disorders; Mental Disorders; Receptors, AMPA
PubMed: 25462292
DOI: 10.1016/j.coph.2014.11.002 -
Proceedings of the National Academy of... Jul 2018Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How mutation leads to intellectual disability, however, is unclear....
Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.
Topics: Animals; Hippocampus; Humans; Long-Term Potentiation; Memory; Mice; N-Acetylglucosaminyltransferases; Protein Transport; Receptors, AMPA
PubMed: 29915039
DOI: 10.1073/pnas.1805060115 -
Proceedings of the Japan Academy.... 2021Psychiatric and neurological disorders severely hamper patient's quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has...
Psychiatric and neurological disorders severely hamper patient's quality of life. Despite their high unmet needs, the development of diagnostics and therapeutics has only made slow progress. This is due to limited evidence on the biological basis of these disorders in humans. Synapses are essential structural units of neurotransmission, and neuropsychiatric disorders are considered as "synapse diseases". Thus, a translational approach with synaptic physiology is crucial to tackle these disorders. Among a variety of synapses, excitatory glutamatergic synapses play central roles in neuronal functions. The glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) is a principal component of glutamatergic neurotransmission; therefore, it is considered to be a promising translational target. Here, we review the limitations of current diagnostics and therapeutics of neuropsychiatric disorders and advocate the urgent need for the promotion of translational medicine based on the synaptic physiology of AMPAR. Furthermore, we introduce our recent translational approach to these disorders by targeting at AMPARs.
Topics: Animals; Humans; Receptors, AMPA; Translational Research, Biomedical
PubMed: 33431723
DOI: 10.2183/pjab.97.001