-
Structure (London, England : 1993) Jun 2023To perform their physiological functions, amino methyl propionic acid receptors (AMPARs) cycle through active, resting, and desensitized states, and dysfunction in AMPAR...
To perform their physiological functions, amino methyl propionic acid receptors (AMPARs) cycle through active, resting, and desensitized states, and dysfunction in AMPAR activity is associated with various neurological disorders. Transitions among AMPAR functional states, however, are largely uncharacterized at atomic resolution and are difficult to examine experimentally. Here, we report long-timescale molecular dynamics simulations of dimerized AMPAR ligand-binding domains (LBDs), whose conformational changes are tightly coupled to changes in AMPAR functional states, in which we observed LBD dimer activation and deactivation upon ligand binding and unbinding at atomic resolution. Importantly, we observed the ligand-bound LBD dimer transition from the active conformation to several other conformations, which may correspond with distinct desensitized conformations. We also identified a linker region whose structural rearrangements heavily affected the transitions to and among these putative desensitized conformations, and confirmed, using electrophysiology experiments, the importance of the linker region in these functional transitions.
Topics: Receptors, AMPA; Ligands; Molecular Dynamics Simulation; Protein Domains; Dimerization
PubMed: 37059095
DOI: 10.1016/j.str.2023.03.013 -
Frontiers in Neural Circuits 2021Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously... (Review)
Review
Excitotoxicity is one of the primary mechanisms of cell loss in a variety of diseases of the central and peripheral nervous systems. Other than the previously established signaling pathways of excitotoxicity, which depend on the excessive release of glutamate from axon terminals or over-activation of NMDA receptors (NMDARs), Ca influx-triggered excitotoxicity through Ca-permeable (CP)-AMPA receptors (AMPARs) is detected in multiple disease models. In this review, both acute brain insults (e.g., brain trauma or spinal cord injury, ischemia) and chronic neurological disorders, including Epilepsy/Seizures, Huntington's disease (HD), Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), chronic pain, and glaucoma, are discussed regarding the CP-AMPAR-mediated excitotoxicity. Considering the low expression or absence of CP-AMPARs in most cells, specific manipulation of the CP-AMPARs might be a more plausible strategy to delay the onset and progression of pathological alterations with fewer side effects than blocking NMDARs.
Topics: Calcium; Glutamic Acid; Humans; Nervous System Diseases; Receptors, AMPA; Receptors, Calcium-Sensing
PubMed: 34483848
DOI: 10.3389/fncir.2021.711564 -
Nature Communications Feb 2022AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains...
AMPA-type glutamate receptors (AMPARs) mediate rapid signal transmission at excitatory synapses in the brain. Glutamate binding to the receptor's ligand-binding domains (LBDs) leads to ion channel activation and desensitization. Gating kinetics shape synaptic transmission and are strongly modulated by transmembrane AMPAR regulatory proteins (TARPs) through currently incompletely resolved mechanisms. Here, electron cryo-microscopy structures of the GluA1/2 TARP-γ8 complex, in both open and desensitized states (at 3.5 Å), reveal state-selective engagement of the LBDs by the large TARP-γ8 loop ('β1'), elucidating how this TARP stabilizes specific gating states. We further show how TARPs alter channel rectification, by interacting with the pore helix of the selectivity filter. Lastly, we reveal that the Q/R-editing site couples the channel constriction at the filter entrance to the gate, and forms the major cation binding site in the conduction path. Our results provide a mechanistic framework of how TARPs modulate AMPAR gating and conductance.
Topics: Animals; Calcium Channels; Cryoelectron Microscopy; Glutamic Acid; HEK293 Cells; Humans; Mutation; Patch-Clamp Techniques; Protein Domains; Rats; Receptors, AMPA; Recombinant Proteins; Synaptic Transmission; Transfection
PubMed: 35136046
DOI: 10.1038/s41467-022-28404-7 -
Science Signaling Feb 2021The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors...
The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor-dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.
Topics: Animals; Ghrelin; Hippocampus; Ligands; Long-Term Potentiation; Memory; Mice; Receptors, AMPA; Receptors, Ghrelin; Signal Transduction
PubMed: 33593997
DOI: 10.1126/scisignal.abb1953 -
Neuropharmacology Nov 2013Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often... (Review)
Review
Since the discovery of long-term potentiation (LTP), thousands of papers have been published on this phenomenon. With this massive amount of information, it is often difficult, especially for someone not directly involved in the field, not to be overwhelmed. The goal of this review is to peel away as many layers as possible, and probe the core properties of LTP. We would argue that the many dozens of proteins that have been implicated in the phenomenon are not essential, but rather modulate, often in indirect ways, the threshold and/or magnitude of LTP. What is required is NMDA receptor activation followed by CaMKII activation. The consequence of CaMKII activation is the rapid recruitment of AMPA receptors to the synapse. This recruitment is independent of AMPA receptor subunit type, but absolutely requires an adequate pool of surface receptors. An important unresolved issue is how exactly CaMKII activation leads to modifications in the PSD to allow rapid enrichment. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.
Topics: Animals; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Long-Term Potentiation; Post-Synaptic Density; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 23439383
DOI: 10.1016/j.neuropharm.2013.02.010 -
The Journal of Neuroscience : the... Sep 2014Cornichon homologs (CNIHs) are AMPA-type glutamate receptor (AMPAR) auxiliary subunits that modulate AMPAR ion channel function and trafficking. Mechanisms underlying...
Cornichon homologs (CNIHs) are AMPA-type glutamate receptor (AMPAR) auxiliary subunits that modulate AMPAR ion channel function and trafficking. Mechanisms underlying this interaction and functional modulation of the receptor complex are currently unclear. Here, using proteins expressed from mouse and rat cDNA, we show that CNIH-3 forms a stable complex with tetrameric AMPARs and contributes to the transmembrane density in single-particle electron microscopy structures. Peptide array-based screening and in vitro mutagenesis identified two clusters of conserved membrane-proximal residues in CNIHs that contribute to AMPAR binding. Because CNIH-1 binds to AMPARs but modulates gating at a significantly lower magnitude compared with CNIH-3, these conserved residues mediate a direct interaction between AMPARs and CNIHs. In addition, residues in the extracellular loop of CNIH-2/3 absent in CNIH-1/4 are critical for both AMPAR interaction and gating modulation. On the AMPAR extracellular domains, the ligand-binding domain and possibly a stretch of linker, connecting the ligand-binding domain to the fourth membrane-spanning segment, is the principal contact point with the CNIH-3 extracellular loop. In contrast, the membrane-distal N-terminal domain is less involved in AMPAR gating modulation by CNIH-3 and AMPAR binding to CNIH-3. Collectively, our results identify conserved residues in the membrane-proximal region of CNIHs that contribute to AMPAR binding and an additional unique segment in the CNIH-2/3 extracellular loop required for both physical interaction and gating modulation of the AMPAR. Consistent with the dissociable properties of binding and gating modulation, we identified a mutant CNIH-3 that preserves AMPAR binding capability but has attenuated activity of gating modulation.
Topics: Amino Acid Sequence; Animals; Binding Sites; Female; HEK293 Cells; Humans; Ion Channel Gating; Male; Molecular Sequence Data; Protein Binding; Rats; Receptors, AMPA
PubMed: 25186755
DOI: 10.1523/JNEUROSCI.0595-14.2014 -
Molecules (Basel, Switzerland) Nov 2022Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative...
Positive allosteric modulators (PAMs) of AMPA receptors represent attractive candidates for the development of drugs for the treatment of cognitive and neurodegenerative disorders. Dimeric molecules have been reported to have an especially potent modulating effect, due to the U-shaped form of the AMPA receptor's allosteric binding site. In the present work, novel bis(pyrimidines) were studied as AMPA receptor modulators. A convenient and flexible preparative approach to bis(pyrimidines) containing a hydroquinone linker was elaborated, and a series of derivatives with varied substituents was obtained. The compounds were examined in the patch clamp experiments for their influence on the kainate-induced currents, and 10 of them were found to have potentiating properties. The best potency was found for 2-methyl-4-(4-((2-methyl-5,6,7,8-tetrahydroquinazolin-4-yl)oxy)phenoxy)-6,7,8,9-tetrahydro-5-cyclohepta[]pyrimidine, which potentiated the kainate-induced currents by up to 77% in all tested concentrations (10-10 M). The results were rationalized via the modeling of modulator complexes with the dimeric ligand binding domain of the GluA2 AMPA receptor, using molecular docking and molecular dynamics simulation. The prediction of ADMET, physicochemical, and PAINS properties of the studied bis(pyrimidines) confirmed that PAMs of this type may act as the potential lead compounds for the development of neuroprotective drugs.
Topics: Receptors, AMPA; Allosteric Regulation; Molecular Docking Simulation; Pyrimidines
PubMed: 36500341
DOI: 10.3390/molecules27238252 -
Drug Discovery Today Dec 2021Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating... (Review)
Review
Glutamatergic transmission is widely implicated in neuropsychiatric disorders, and the discovery that ketamine elicits rapid-acting antidepressant effects by modulating α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) signaling has spurred a resurgence of interest in the field. This review explores agents in various stages of development for neuropsychiatric disorders that positively modulate AMPARs, both directly and indirectly. Despite promising preclinical research, few direct and indirect AMPAR positive modulators have progressed past early clinical development. Challenges such as low potency have created barriers to effective implementation. Nevertheless, the functional complexity of AMPARs sets them apart from other drug targets and allows for specificity in drug discovery. Additional effective treatments for neuropsychiatric disorders that work through positive AMPAR modulation may eventually be developed.
Topics: Animals; Antidepressive Agents; Drug Development; Drug Discovery; Humans; Ketamine; Mental Disorders; Receptors, AMPA
PubMed: 34358693
DOI: 10.1016/j.drudis.2021.07.027 -
The Journal of Physiology Jan 2015During the past decade, considerable evidence has accumulated that non-NMDA glutamate receptors (both AMPA and kainate subtypes) are modulated by the association of the... (Review)
Review
During the past decade, considerable evidence has accumulated that non-NMDA glutamate receptors (both AMPA and kainate subtypes) are modulated by the association of the core tetrameric receptor with auxiliary proteins that are integral components of native receptor assemblies. This short review focuses on the effect of two types of auxiliary subunits on the biophysical properties and kinetic behaviour of AMPA and kainate receptors at the level of single receptor molecules. Type I transmembrane AMPA receptor proteins increase the number of AMPA receptor openings that result from a single receptor activation as well as the proportion of openings to conductance levels above 30 pS, resulting in larger peak ensemble currents that decay more slowly and bi-exponentially. Co-expression of Neto1 and 2 with pore-forming kainate receptor subunits also increases the duration of bursts and destabilizes desensitized states, resulting in a rapid component of recovery and clusters of bursts that produce a slow component in desensitization decays. The distinct gating seen in the presence of auxiliary subunits reflects slow switching between gating modes with different single-channel kinetics and open probability. At any given time, the relative proportions of receptors in each gating mode determine both the shape and the amplitude of synaptic currents.
Topics: Humans; Ion Channel Gating; Protein Subunits; Receptors, AMPA; Receptors, Kainic Acid
PubMed: 25556788
DOI: 10.1113/jphysiol.2014.273904 -
ELife Feb 2023Intracellular trafficking of AMPA receptors is a tightly regulated process which involves several adaptor proteins, and is crucial for the activity of excitatory...
Intracellular trafficking of AMPA receptors is a tightly regulated process which involves several adaptor proteins, and is crucial for the activity of excitatory synapses both in basal conditions and during synaptic plasticity. We found that, in rat hippocampal neurons, an intracellular pool of the tetraspanin TSPAN5 promotes exocytosis of AMPA receptors without affecting their internalisation. TSPAN5 mediates this function by interacting with the adaptor protein complex AP4 and Stargazin and possibly using recycling endosomes as a delivery route. This work highlights TSPAN5 as a new adaptor regulating AMPA receptor trafficking.
Topics: Animals; Rats; Adaptor Proteins, Signal Transducing; Exocytosis; Hippocampus; Neuronal Plasticity; Protein Transport; Receptors, AMPA; Synapses; Tetraspanins
PubMed: 36795458
DOI: 10.7554/eLife.76425