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Biomolecules Dec 2022L-Glutamic acid is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors localized on neuronal and non-neuronal cells... (Review)
Review
L-Glutamic acid is the main excitatory neurotransmitter in the central nervous system (CNS). Its associated receptors localized on neuronal and non-neuronal cells mediate rapid excitatory synaptic transmission in the CNS and regulate a wide range of processes in the brain, spinal cord, retina, and peripheral nervous system. In particular, the glutamate receptors selective to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) also play an important role in numerous neurological disorders and attract close attention as targets for the creation of new classes of drugs for the treatment or substantial correction of a number of serious neurodegenerative and neuropsychiatric diseases. For this reason, the search for various types of AMPA receptor ligands and studies of their properties are attracting considerable attention both in academic institutions and in pharmaceutical companies around the world. This review focuses mainly on the advances in this area published since 2017. Particular attention is paid to the structural diversity of new chemotypes of agonists, competitive AMPA receptor antagonists, positive and negative allosteric modulators, transmembrane AMPA regulatory protein (TARP) dependent allosteric modulators, ion channel blockers as well as their binding sites. This review also presents the studies of the mechanisms of action of AMPA receptor ligands that mediate their therapeutic effects.
Topics: Receptors, AMPA; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Receptors, Glutamate; Brain; Glutamic Acid
PubMed: 36671441
DOI: 10.3390/biom13010056 -
Current Opinion in Neurobiology Aug 2017Modulation of synaptic strength through trafficking of AMPA receptors is a fundamental mechanism underlying synaptic plasticity and has been shown to be an important... (Review)
Review
Modulation of synaptic strength through trafficking of AMPA receptors is a fundamental mechanism underlying synaptic plasticity and has been shown to be an important process in higher brain functions such as learning and memory. Many studies have used live time-lapse imaging of fluorescently tagged AMPA receptors to directly monitor their membrane trafficking in the basal state as well as during synaptic plasticity. While most of these studies are performed in vitro using neuronal cell cultures, in the past years technological advances have enabled the imaging of synaptic proteins in vivo in intact organisms. This has allowed for visualization of synaptic plasticity on a molecular level in living and behaving animals. Here, we discuss key studies and approaches using dynamic imaging to visualize AMPA receptor trafficking in vitro as well as imaging synaptic proteins, including AMPA receptors, in vivo.
Topics: Animals; Cells, Cultured; Fluorescent Dyes; Intravital Microscopy; Optical Imaging; Protein Transport; Receptors, AMPA; Synapses; Time-Lapse Imaging
PubMed: 28411409
DOI: 10.1016/j.conb.2017.03.008 -
Nature Communications Oct 2023Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that...
Transmembrane AMPA receptor regulatory proteins (TARPs) and germ cell-specific gene 1-like protein (GSG1L) are claudin-type AMPA receptor (AMPAR) auxiliary subunits that profoundly regulate glutamatergic synapse strength and plasticity. While AMPAR-TARP complexes have been extensively studied, less is known about GSG1L-containing AMPARs. Here, we show that GSG1L's spatiotemporal expression, native interactome and allosteric sites are distinct. GSG1L generally expresses late during brain development in a region-specific manner, constituting about 5% of all AMPAR complexes in adulthood. While GSG1L can co-assemble with TARPs or cornichons (CNIHs), it also assembles as the sole auxiliary subunit. Unexpectedly, GSG1L acts through two discrete evolutionarily-conserved sites on the agonist-binding domain with a weak allosteric interaction at the TARP/KGK site to slow desensitization, and a stronger interaction at a different site that slows recovery from desensitization. Together, these distinctions help explain GSG1L's evolutionary past and how it fulfills a unique signaling role within glutamatergic synapses.
Topics: Receptors, AMPA; Allosteric Site; Proteins; Synapses
PubMed: 37884493
DOI: 10.1038/s41467-023-42517-7 -
Current Opinion in Neurobiology Jun 2012In the mammalian central nervous system, the majority of fast excitatory synaptic transmission is mediated by glutamate acting on AMPA-type ionotropic glutamate... (Review)
Review
In the mammalian central nervous system, the majority of fast excitatory synaptic transmission is mediated by glutamate acting on AMPA-type ionotropic glutamate receptors. The abundance of AMPA receptors at the synapse can be modulated through receptor trafficking, which dynamically regulates many fundamental brain functions, including learning and memory. Reversible posttranslational modifications, including phosphorylation, palmitoylation and ubiquitination of AMPA receptor subunits are important regulatory mechanisms for controlling synaptic AMPA receptor expression and function. In this review, we highlight recent advances in the study of AMPA receptor posttranslational modifications and discuss how these modifications regulate AMPA receptor trafficking and function at synapses.
Topics: Animals; Models, Biological; Protein Biosynthesis; Protein Transport; Receptors, AMPA; Synapses
PubMed: 22000952
DOI: 10.1016/j.conb.2011.09.008 -
Neuro-SignalsAMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission in the mammalian brain. It is widely believed that the long-lasting,... (Review)
Review
AMPA-type glutamate receptors (AMPARs) mediate most fast excitatory synaptic transmission in the mammalian brain. It is widely believed that the long-lasting, activity-dependent changes in synaptic strength, including long-term potentiation and long-term depression, could be the molecular and cellular basis of experience-dependent plasticities, such as learning and memory. Those changes of synaptic strength are directly related to AMPAR trafficking to and away from the synapse. There are many forms of synaptic plasticity in the mammalian brain, while the prototypic form, hippocampal CA1 long-term potentiation, has received the most intense investigation. After synthesis, AMPAR subunits undergo posttranslational modifications such as glycosylation, palmitoylation, phosphorylation and potential ubiquitination. In addition, AMPAR subunits spatiotemporally associate with specific neuronal proteins in the cell. Those posttranslational modifications and receptor-associated proteins play critical roles in AMPAR trafficking and regulation of AMPAR-dependent synaptic plasticity. Here, we summarize recent studies on posttranslational modifications and associated proteins of AMPAR subunits, and their roles in receptor trafficking and synaptic plasticity.
Topics: Animals; Membrane Proteins; Models, Biological; Neuronal Plasticity; Protein Processing, Post-Translational; Protein Transport; Receptors, AMPA; Synapses
PubMed: 17622793
DOI: 10.1159/000105517 -
Cell Sep 2017AMPA receptors mediate fast excitatory neurotransmission in the mammalian brain and transduce the binding of presynaptically released glutamate to the opening of a...
AMPA receptors mediate fast excitatory neurotransmission in the mammalian brain and transduce the binding of presynaptically released glutamate to the opening of a transmembrane cation channel. Within the postsynaptic density, however, AMPA receptors coassemble with transmembrane AMPA receptor regulatory proteins (TARPs), yielding a receptor complex with altered gating kinetics, pharmacology, and pore properties. Here, we elucidate structures of the GluA2-TARP γ2 complex in the presence of the partial agonist kainate or the full agonist quisqualate together with a positive allosteric modulator or with quisqualate alone. We show how TARPs sculpt the ligand-binding domain gating ring, enhancing kainate potency and diminishing the ensemble of desensitized states. TARPs encircle the receptor ion channel, stabilizing M2 helices and pore loops, illustrating how TARPs alter receptor pore properties. Structural and computational analysis suggests the full agonist and modulator complex harbors an ion-permeable channel gate, providing the first view of an activated AMPA receptor.
Topics: Animals; Calcium Channels; Cryoelectron Microscopy; Excitatory Amino Acid Agonists; Kainic Acid; Models, Molecular; Quisqualic Acid; Rats; Receptors, AMPA
PubMed: 28823560
DOI: 10.1016/j.cell.2017.07.045 -
Neuroscience Sep 2009Heterogeneity among AMPA receptor (AMPAR) subtypes is thought to be one of the key postsynaptic factors giving rise to diversity in excitatory synaptic signaling in the... (Review)
Review
Heterogeneity among AMPA receptor (AMPAR) subtypes is thought to be one of the key postsynaptic factors giving rise to diversity in excitatory synaptic signaling in the CNS. Recently, compelling evidence has emerged that ancillary AMPAR subunits-the so-called transmembrane AMPA receptor regulatory proteins (TARPs)-also play a vital role in influencing the variety of postsynaptic signaling. This TARP family of molecules controls both trafficking and functional properties of AMPARs at most, if not all, excitatory central synapses. Furthermore, individual TARPs differ in their effects on the biophysical and pharmacological properties of AMPARs. The critical importance of TARPs in synaptic transmission was first revealed in experiments on cerebellar granule cells from stargazer mice. These lack the prototypic TARP stargazin, present in granule cells from wild-type animals, and consequently lack synaptic transmission at the mossy fibre-to-granule cell synapse. Subsequent work has identified many other members of the stargazin family which act as functional TARPs. It has also provided valuable information about specific TARPs present in many central neurons. Because much of the initial work on TARPs was carried out on stargazer granule cells, the important functional properties of TARPs present throughout the cerebellum have received particular attention. Here we discuss some of these recent findings in relation to the main TARPs and the AMPAR subunits identified in cerebellar neurons and glia.
Topics: Animals; Cerebellum; Membrane Proteins; Neurons; Protein Transport; Receptors, AMPA; Synaptic Transmission
PubMed: 19185052
DOI: 10.1016/j.neuroscience.2009.01.004 -
The Journal of Neuroscience : the... Oct 2018The spatiotemporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus of information... (Review)
Review
The spatiotemporal organization of neurotransmitter receptors in the postsynaptic membrane is a fundamental determinant of synaptic transmission and thus of information processing by the brain. The ionotropic AMPA subtype of glutamate receptors (AMPARs) mediate fast excitatory synaptic transmission in the CNS. The number of AMPARs located en face presynaptic glutamate release sites sets the efficacy of synaptic transmission. Understanding how this number is set and regulated has been the topic of intense research in the last two decades. We showed that AMPARs are not stable in the synapse as initially thought. They continuously enter and exit the postsynaptic density by lateral diffusion, and they exchange between the neuronal surface and intracellular compartments by endocytosis and exocytosis at extrasynaptic sites. Regulation of these various trafficking pathways has emerged as a key mechanism for activity-dependent plasticity of synaptic transmission, a process important for learning and memory. I here present my view of these findings. In particular, the advent of super-resolution microscopy and single-molecule tracking has helped to uncover the intricacy of AMPARs' dynamic organization at the nanoscale. In addition, AMPAR surface diffusion is highly regulated by a variety of factors, including neuronal activity, stress hormones, and neurodegeneration, suggesting that AMPAR diffusion-trapping may play a central role in synapse function. Using innovative tools to understand further the link between receptor dynamics and synapse plasticity is now unveiling new molecular mechanisms of learning. Modifying AMPAR dynamics may emerge as a new target to correct synapse dysfunction in the diseased brain.
Topics: Animals; Humans; Learning; Nanotechnology; Neuronal Plasticity; Protein Structure, Secondary; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 30381423
DOI: 10.1523/JNEUROSCI.2119-18.2018 -
Trends in Pharmacological Sciences Jul 2008Presynaptic glutamate release elicits brief waves of membrane depolarization in neurons by activating AMPA receptors. Depending on its precise size and shape, current... (Review)
Review
Presynaptic glutamate release elicits brief waves of membrane depolarization in neurons by activating AMPA receptors. Depending on its precise size and shape, current through AMPA receptors gates downstream processes like NMDA receptor activation and action potential generation. Over a decade of research on AMPA receptor structure and function has identified binding sites on AMPA receptors for agonists, antagonists and allosteric modulators as well as key residues underlying differences in the gating behavior of various AMPA receptor subtypes. However, the recent discovery that AMPA receptors are accompanied in the synaptic membrane by a family of auxiliary subunits known as transmembrane AMPA receptor regulatory proteins (TARPs) has revealed that the kinetics and pharmacology of neuronal AMPA receptors differ in many respects from those predicted by classical studies of AMPA receptors in heterologous systems. Here, we summarize recent work and discuss remaining questions concerning the structure and function of native TARP-AMPA receptor complexes.
Topics: 6-Cyano-7-nitroquinoxaline-2,3-dione; Allosteric Regulation; Animals; Binding Sites; Calcium Channels; Humans; Ion Channel Gating; Kainic Acid; Nuclear Proteins; Protein Subunits; Receptors, AMPA
PubMed: 18514334
DOI: 10.1016/j.tips.2008.04.004 -
Current Opinion in Neurobiology Jun 2012AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic... (Review)
Review
AMPA receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the brain. Dynamic changes in neuronal synaptic efficacy, termed synaptic plasticity, are thought to underlie information coding and storage in learning and memory. One major mechanism that regulates synaptic strength involves the tightly regulated trafficking of AMPARs into and out of synapses. The life cycle of AMPARs from their biosynthesis, membrane trafficking, and synaptic targeting to their degradation are controlled by a series of orchestrated interactions with numerous intracellular regulatory proteins. Here we review recent progress made toward the understanding the regulation of AMPAR trafficking, focusing on the roles of several key intracellular AMPAR interacting proteins.
Topics: Animals; Models, Biological; Neuronal Plasticity; Protein Transport; Receptors, AMPA; Synapses
PubMed: 22217700
DOI: 10.1016/j.conb.2011.12.006