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Transcriptomic expression of AMPA receptor subunits and their auxiliary proteins in the human brain.Neuroscience Letters Jun 2021Receptors to glutamate of the AMPA type (AMPARs) serve as the major gates of excitation in the human brain, where they participate in fundamental processes underlying... (Review)
Review
Receptors to glutamate of the AMPA type (AMPARs) serve as the major gates of excitation in the human brain, where they participate in fundamental processes underlying perception, cognition and movement. Due to their central role in brain function, dysregulation of these receptors has been implicated in neuropathological states associated with a large variety of diseases that manifest with abnormal behaviors. The participation of functional abnormalities of AMPARs in brain disorders is strongly supported by genomic, transcriptomic and proteomic studies. Most of these studies have focused on the expression and function of the subunits that make up the channel and define AMPARs (GRIA1-GRIA4), as well of some accessory proteins. However, it is increasingly evident that native AMPARs are composed of a complex array of accessory proteins that regulate their trafficking, localization, kinetics and pharmacology, and a better understanding of the diversity and regional expression of these accessory proteins is largely needed. In this review we will provide an update on the state of current knowledge of AMPA receptors subunits in the context of their accessory proteins at the transcriptome level. We also summarize the regional expression in the human brain and its correlation with the channel forming subunits. Finally, we discuss some of the current limitations of transcriptomic analysis and propose potential ways to overcome them.
Topics: Brain; Gene Expression; Humans; Protein Subunits; Receptors, AMPA; Transcriptome
PubMed: 33915226
DOI: 10.1016/j.neulet.2021.135938 -
ELife Oct 2017Ion conductivity and the gating characteristics of tetrameric glutamate receptor ion channels are determined by their subunit composition. Competitive homo- and...
Ion conductivity and the gating characteristics of tetrameric glutamate receptor ion channels are determined by their subunit composition. Competitive homo- and hetero-dimerization of their amino-terminal domains (ATDs) is a key step controlling assembly. Here we measured systematically the thermodynamic stabilities of homodimers and heterodimers of kainate and AMPA receptors using fluorescence-detected sedimentation velocity analytical ultracentrifugation. Measured affinities span many orders of magnitude, and complexes show large differences in kinetic stabilities. The association of kainate receptor ATD dimers is generally weaker than the association of AMPA receptor ATD dimers, but both show a general pattern of increased heterodimer stability as compared to the homodimers of their constituents, matching well physiologically observed receptor combinations. The free energy maps of AMPA and kainate receptor ATD dimers provide a framework for the interpretation of observed receptor subtype combinations and possible assembly pathways.
Topics: HEK293 Cells; Humans; Kinetics; Protein Multimerization; Protein Stability; Protein Subunits; Receptors, AMPA; Receptors, Kainic Acid; Thermodynamics; Ultracentrifugation
PubMed: 29058671
DOI: 10.7554/eLife.32056 -
The Journal of Physiology Jan 2021
Topics: Ion Channels; Neurotransmitter Agents; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 33448020
DOI: 10.1113/JP280800 -
Philosophical Transactions of the Royal... Apr 2003Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms... (Review)
Review
Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms have been the subject of considerable scrutiny over the past few decades. I review studies from our laboratory that support a critical role for AMPA receptor trafficking in LTP and experience-dependent plasticity.
Topics: Animals; Electrophysiology; Homeostasis; Long-Term Potentiation; Neuronal Plasticity; Phosphorylation; Receptors, AMPA; Recombinant Proteins; Synapses
PubMed: 12740116
DOI: 10.1098/rstb.2002.1233 -
Small GTPases Nov 2019Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is... (Review)
Review
Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.
Topics: Animals; Neuronal Plasticity; Neurons; Protein Transport; Receptors, AMPA; rab GTP-Binding Proteins
PubMed: 28628388
DOI: 10.1080/21541248.2017.1337546 -
The Journal of Biological Chemistry Oct 2020α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)-type glutamate receptors (AMPARs) are the predominant excitatory neurotransmitter receptors in the brain,...
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA)-type glutamate receptors (AMPARs) are the predominant excitatory neurotransmitter receptors in the brain, where they mediate synaptic transmission and plasticity. Excessive AMPAR activation leads to diseases such as epilepsy. AMPAR properties are modulated by auxiliary proteins and foremost by the transmembrane AMPAR regulatory proteins (TARPs). These distribute in unique expression patterns across the brain, rendering AMPAR/TARP complexes promising targets for region-specific therapeutic intervention. TARP γ8 is predominantly expressed in the forebrain and is enriched in the hippocampus, a region associated with temporal lobe epilepsy. Recent high-throughput medicinal chemistry screens have identified multiple promising compounds that selectively target AMPARs associated with γ8 and hold promise for epilepsy treatment. However, how these modulators target the receptor complex is currently unknown. Here, we use a combination of ligand docking, molecular dynamics simulations, and electrophysiology to address this question. We identify a conserved oxindole isostere, shared between three structurally diverse modulators (LY-3130481, JNJ-55511118, and JNJ-61432059) as the major module engaging γ8 by an H-bond to Asn-172 (γ8). The remaining variable region of each molecule likely targets the receptor complex in ligand-selective modes. Functional data reveal parallels in the underlying modulatory action of two prominent compounds. This work will aid development of refined AMPAR epilepsy therapeutics and facilitate to uncover the mechanisms by which TARPs modulate the receptor.
Topics: Animals; Benzimidazoles; Binding Sites; Calcium Channels; HEK293 Cells; Humans; Ligands; Models, Molecular; Molecular Docking Simulation; Oxindoles; Protein Binding; Protein Interaction Maps; Rats; Receptors, AMPA
PubMed: 32747446
DOI: 10.1074/jbc.RA120.014135 -
International Journal of Molecular... Mar 2019α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are assembled of four core subunits and several additional interacting proteins. Cystine-knot AMPA... (Review)
Review
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are assembled of four core subunits and several additional interacting proteins. Cystine-knot AMPA receptor-modulating proteins (CKAMPs) constitute a family of four proteins that influence the trafficking, subcellular localization and function of AMPA receptors. The four CKAMP family members CKAMP39/shisa8, CKAMP44/shisa9, CKAMP52/shisa6 and CKAMP59/shisa7 differ in their expression profile and their modulatory influence on AMPA receptor function. In this review, I report about recent findings on the differential roles of CKAMP family members.
Topics: Amino Acid Sequence; Animals; Carrier Proteins; Cell Line; Gene Expression; Geniculate Bodies; Hippocampus; Humans; Ion Channel Gating; Multigene Family; Neuronal Plasticity; Protein Binding; Protein Transport; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 30909450
DOI: 10.3390/ijms20061460 -
The Journal of Physiology Jan 2022Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at... (Review)
Review
Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at excitatory synapses, and conventional wisdom says that they activate in hundreds of microseconds, deactivate in milliseconds due to their low affinity for glutamate and also desensitize profoundly. These properties circumscribe AMPA receptor activation in both space and time. However, accumulating evidence shows that AMPA receptors can also activate with slow, indefatigable responses. They do so through interactions with auxiliary subunits that are able promote a switch to a high open probability, high-conductance 'superactive' mode. In this review, we show that any assumption that this phenomenon is limited to heterologous expression is false and rather that slow AMPA currents have been widely and repeatedly observed throughout the nervous system. Hallmarks of the superactive mode are a lack of desensitization, resistance to competitive antagonists and a current decay that outlives free glutamate by hundreds of milliseconds. Because the switch to the superactive mode is triggered by activation, AMPA receptors can generate accumulating 'pedestal' currents in response to repetitive stimulation, constituting a postsynaptic mechanism for short-term potentiation in the range 5-100 Hz. Further, slow AMPA currents span 'cognitive' time intervals in the 100 ms range (theta rhythms), of particular interest for hippocampal function, where slow AMPA currents are widely expressed in a synapse-specific manner. Here, we outline the implications that slow AMPA receptors have for excitatory synaptic transmission and computation in the nervous system.
Topics: Glutamic Acid; Patch-Clamp Techniques; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 34587649
DOI: 10.1113/JP280877 -
Neuron Mar 2007AMPA receptors (AMPARs) conduct fast, excitatory currents that depolarize neurons and trigger action potentials. AMPARs took on new importance when it was shown that... (Review)
Review
AMPA receptors (AMPARs) conduct fast, excitatory currents that depolarize neurons and trigger action potentials. AMPARs took on new importance when it was shown that AMPAR transport can increase or decrease the number of AMPARs at synapses and give rise to synapse plasticity, including long-term potentiation (LTP) and long-term depression (LTD). This review considers how transmembrane AMPAR regulatory proteins (TARPs), a novel family of AMPAR auxiliary subunits, have changed our view of AMPAR transport and raised some perplexing questions.
Topics: Animals; Calcium Channels; Mice; Mice, Neurologic Mutants; Protein Structure, Tertiary; Protein Transport; Receptors, AMPA
PubMed: 17329203
DOI: 10.1016/j.neuron.2007.02.006 -
International Journal of Molecular... Oct 2023Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by... (Review)
Review
Autoantibodies against NMDA and AMPA receptors have been identified in the central nervous system of patients suffering from brain disorders characterized by neurological and psychiatric symptoms. It has been demonstrated that these autoantibodies can affect the functions and/or the expression of the targeted receptors, altering synaptic communication. The importance to clarify, in preclinical models, the molecular mechanisms involved in the autoantibody-mediated effects has emerged in order to understand their pathogenic role in central disorders, but also to propose new therapeutic approaches for preventing the deleterious central consequences. In this review, we describe some of the available preclinical literature concerning the impact of antibodies recognizing NMDA and AMPA receptors in neurons. This review discusses the cellular events that would support the detrimental roles of the autoantibodies, also illustrating some contrasting findings that in our opinion deserve attention and further investigations before translating the preclinical observations to clinic.
Topics: Humans; Receptors, AMPA; N-Methylaspartate; Receptors, N-Methyl-D-Aspartate; Neurons; Autoantibodies
PubMed: 37834353
DOI: 10.3390/ijms241914905