Hubbry Logo
AMPA receptorAMPA receptorMain
Open search
AMPA receptor
Community hub
AMPA receptor
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
AMPA receptor
AMPA receptor
AMPA receptor
View on Wikipedia
from Wikipedia
The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor, AMPAR, or quisqualate receptor) is an ionotropic glutamate receptor (iGluR) and predominantly sodium ion channel that mediates fast excitatory neurotransmission in the central nervous system (CNS).[1] Its activation by the neurotransmitter glutamate facilitates rapid neuronal communication, essential for various brain functions, including learning and memory.[2] Its name is derived from the ability to be activated by the artificial glutamate analog AMPA. The receptor was initially named the "quisqualate receptor" by Watkins and colleagues after the naturally occurring agonist quisqualate.[3] Later, the receptor was designated as the "AMPA receptor" following the development of the selective agonist AMPA by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen.[3] The GRIA2-encoded AMPA receptor ligand binding core (GluA2 LBD) was the first glutamate receptor ion channel domain to be crystallized.[4]

Structure and function

[edit]

Subunit composition

[edit]

AMPARs are composed of four types of subunits encoded by different genes, designated as GRIA1 (GluA1 or GluR1), GRIA2 (GluA2 or GluR2), GRIA3 (GluA3 or GluR3), and GRIA4 (GluA4 or GluRA-D2), which combine to form a tetrameric structure.[5][6][7] Most AMPARs are heterotetrameric, consisting of symmetric 'dimer of dimers' of GluA2 and either GluA1, GluA3 or GluA4.[8][9] Dimerization starts in the endoplasmic reticulum with the interaction of N-terminal LIVBP domains, then "zips up" through the ligand-binding domain into the transmembrane ion pore.[9]

The conformation of the subunit protein in the plasma membrane caused controversy for some time. While the amino acid sequence of the subunit indicated that there seemed to be four transmembrane protein domains (parts of the protein that pass through the plasma membrane), proteins interacting with the subunit indicated that the N-terminus were extracellular, while the C-terminus were intracellular. However, if each of the four transmembrane domains went all the way through the plasma membrane, then the two termini would have to be on the same side of the membrane. It was eventually discovered that the second "transmembrane" domain (M2) does not fully traverse the membrane but instead forms a reentrant helix-loop, contributing to the ion-conducting pore of the receptor.[10] The domain kinks back on itself within the membrane and returns to the intracellular side.[11] When the four subunits of the tetramer come together, this second membranous domain forms the ion-permeable pore of the receptor. The M2 loop plays a crucial role in forming the ion channel's selectivity filter, with the helical portions of M2 contributing to hydrophobic interfaces between AMPAR subunits in the ion channel.[12]

AMPAR subunits differ most in their C-terminal sequence, which determines their interactions with scaffolding proteins. All AMPARs contain PDZ-binding domains, but which PDZ domain they bind to differs. For example, GluA1 binds to SAP97 through SAP97's class I PDZ domain,[13] while GluA2 binds to PICK1[14] and GRIP/ABP. Of note, AMPARs cannot directly bind to the common synaptic protein PSD-95 owing to incompatible PDZ domains, although they do interact with PSD-95 via stargazin (the prototypical member of the TARP family of AMPAR auxiliary subunits).[15]

Phosphorylation of AMPARs can regulate channel localization, conductance, and open probability. GluA1 has four known phosphorylation sites at serine 818 (S818), S831, threonine 840, and S845 (other subunits have similar phosphorylation sites, but GluR1 has been the most extensively studied). S818 is phosphorylated by protein kinase C (PKC) and is necessary for long-term potentiation (LTP; for GluA1's role in LTP, see below).[16] S831 is phosphorylated by CaMKII and PKC during LTP, which helps deliver GluA1-containing AMPAR to the synapse,[17] and increases their single channel conductance.[18] The T840 site was more recently discovered, and has been implicated in LTD.[19] Finally, S845 is phosphorylated by protein kinase A (PKA) which regulates its open probability.[20]

Mechanism of Action

[edit]

AMPA receptors are integral to fast excitatory neurotransmission in the CNS. Each receptor is a tetramer composed of four subunits, each providing a binding site for agonists like glutamate.[8] The ligand-binding domain is formed by the N-terminal tail and the extracellular loop between transmembrane domains three and four.[21] The subunit composition significantly influences the receptor's functional properties, including ion permeability and gating kinetics.

Agonist Binding and Channel Activation

[edit]

Upon glutamate binding, these two loops move towards each other, leading to pore opening. The channel opens when two sites are occupied,[22] and increases its current as more binding sites are occupied.[23] This opening allows the influx of sodium (Na⁺) and, depending on subunit composition, calcium (Ca²⁺) ions into the postsynaptic neuron, leading to depolarization and the propagation of excitatory signals.[24] Once open, the channel may undergo rapid desensitization, stopping the current.

Desensitization Mechanism

[edit]

The mechanism of desensitization is due to a small change in angle of one of the parts of the binding site, closing the pore.[25] AMPARs open and close quickly (1ms), and are thus responsible for most of the fast excitatory postsynaptic transmission in the central nervous system.[22]

Subunit Composition and Ion Permeability

[edit]

The AMPAR's permeability to calcium and other cations, such as sodium and potassium, is governed by the GluA2 subunit. If an AMPAR lacks a GluA2 subunit, then it will be permeable to sodium, potassium, and calcium. The presence of a GluA2 subunit will render the channel impermeable to calcium. This is determined by post-transcriptional modification — RNA editing — of the Q-to-R editing site of the GluA2 mRNA. Here, A→I editing alters the uncharged amino acid glutamine (Q) to the positively charged arginine (R) in the receptor's ion channel. The positively charged amino acid at the critical point makes it energetically unfavorable for calcium to enter the cell through the pore.[26] Almost all of the GluA2 subunits in CNS are edited to the GluA2(R) form. This means that the principal ions gated by AMPARs are sodium and potassium, distinguishing AMPARs from NMDA receptors (the other main ionotropic glutamate receptors in the brain), which also permit calcium influx. Both AMPA and NMDA receptors, however, have an equilibrium potential near 0 mV. The prevention of calcium entry into the cell on activation of GluA2-containing AMPARs is proposed to guard against excitotoxicity.[27] The subunit composition of the AMPAR is also important for the way this receptor is modulated. If an AMPAR lacks GluA2 subunits, then it is susceptible to being blocked in a voltage-dependent manner by a class of molecules called polyamines. Thus, when the neuron is at a depolarized membrane potential, polyamines will block the AMPAR channel more strongly, preventing the flux of potassium ions through the channel pore. GluA2-lacking AMPARs are, thus, said to have an inwardly rectifying I/V curve, which means that they pass less outward current than inward current at equivalent distance from the reversal potential.[28] Calcium permeable AMPARs are found typically early during postnatal development on neocortical pyramidal neurons,[28] some interneurons, or in dopamine neurons of the ventral tegmental area after the exposure to an addictive drug.[29]

Alongside RNA editing, alternative splicing allows a range of functional AMPA receptor subunits beyond what is encoded in the genome. In other words, although one gene (GRIA1–GRIA4) is encoded for each subunit (GluA1–GluA4), splicing after transcription from DNA allows some exons to be translated interchangeably, leading to several functionally different subunits from each gene.[30]

The flip/flop sequence is one such interchangeable exon. A 38-amino acid sequence found prior to (i.e., before the N-terminus of) the fourth membranous domain in all four AMPAR subunits, it determines the speed of desensitization[31] of the receptor and also the speed at which the receptor is resensitized[32] and the rate of channel closing.[33] The flip form is present in prenatal AMPA receptors and gives a sustained current in response to glutamate activation.[34]

Synaptic plasticity

[edit]

AMPA receptors (AMPAR) are both glutamate receptors and cation channels that are integral to plasticity and synaptic transmission at many postsynaptic membranes. One of the most widely and thoroughly investigated forms of plasticity in the nervous system is known as long-term potentiation (LTP). There are two necessary components of LTP: presynaptic glutamate release and postsynaptic depolarization. Therefore, LTP can be induced experimentally in a paired electrophysiological recording when a presynaptic cell is stimulated to release glutamate on a postsynaptic cell that is depolarized. The typical LTP induction protocol involves a "tetanus" stimulation, which is a 100-Hz stimulation for 1 second. When one applies this protocol to a pair of cells, one will see a sustained increase of the amplitude of the excitatory postsynaptic potential (EPSP) following tetanus. This response is interesting because it is thought to be the physiological correlation for learning and memory in the cell. In fact, it has been shown that, following a single paired-avoidance paradigm in mice, LTP can be recorded in some hippocampal synapses in vivo.[35]

The molecular basis for LTP has been extensively studied, and AMPARs have been shown to play an integral role in the process. Both GluR1 and GluR2 play an important role in synaptic plasticity. It is now known that the underlying physiological correlation for the increase in EPSP size is a postsynaptic upregulation of AMPARs at the membrane,[36] which is accomplished through the interactions of AMPARs with many cellular proteins.

The simplest explanation for LTP is as follows (see the long-term potentiation article for a much more detailed account). Glutamate binds to postsynaptic AMPARs and another glutamate receptor, the NMDA receptor (NMDAR). Ligand binding causes the AMPARs to open, and Na+ flows into the postsynaptic cell, resulting in a depolarization. NMDARs, on the other hand, do not open directly because their pores are occluded at resting membrane potential by Mg2+ ions. NMDARs can open only when a depolarization from the AMPAR activation leads to repulsion of the Mg2+ cation out into the extracellular space, allowing the pore to pass current. Unlike AMPARs, however, NMDARs are permeable to both Na+ and Ca2+. The Ca2+ that enters the cell triggers the upregulation of AMPARs to the membrane, which results in a long-lasting increase in EPSP size underlying LTP. The calcium entry also phosphorylates CaMKII, which phosphorylates AMPARs, increasing their single-channel conductance.

AMPA receptor trafficking

[edit]
Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli
Regulation of AMPAR trafficking to the postsynaptic density in response to LTP-inducing stimuli

Molecular and signaling response to LTP-inducing stimuli

[edit]

The mechanism for LTP has long been a topic of debate, but, recently, mechanisms have come to some consensus. AMPARs play a key role in this process, as one of the key indicators of LTP induction is the increase in the ratio of AMPAR to NMDARs following high-frequency stimulation. The idea is that AMPARs are trafficked from the dendrite into the synapse and incorporated through some series of signaling cascades.

AMPARs are initially regulated at the transcriptional level at their 5' promoter regions. There is significant evidence pointing towards the transcriptional control of AMPA receptors in longer-term memory through cAMP response element-binding protein (CREB) and mitogen-activated protein kinases (MAPK).[37] Messages are translated on the rough endoplasmic reticulum (rough ER) and modified there. Subunit compositions are determined at the time of modification at the rough ER.[14] After post-ER processing in the Golgi apparatus, AMPARs are released into the perisynaptic membrane as a reserve waiting for the LTP process to be initiated.

The first key step in the process following glutamate binding to NMDARs is the influx of calcium through the NMDA receptors and the resultant activation of Ca2+/calmodulin-dependent protein kinase (CaMKII).[38] Blocking either this influx or the activation of CaMKII prevents LTP, showing that these are necessary mechanisms for LTP.[39] In addition, profusion of CaMKII into a synapse causes LTP, showing that it is a causal and sufficient mechanism.[40]

CaMKII has multiple modes of activation to cause the incorporation of AMPA receptors into the perisynaptic membrane. CAMKII enzyme is eventually responsible for the development of the actin cytoskeleton of neuronal cells and, eventually, for the dendrite and axon development (synaptic plasticity).[41] The first is direct phosphorylation of synaptic-associated protein 97 (SAP97), a scaffolding protein.[42] First, SAP-97 and Myosin-VI, a motor protein, are bound as a complex to the C-terminus of AMPARs. Following phosphorylation by CaMKII, the complex moves into the perisynaptic membrane.[43] The second mode of activation is through the MAPK pathway. CaMKII activates the Ras proteins, which go on to activate p42/44 MAPK, which drives AMPAR insertion directly into the perisynaptic membrane.[44]

AMPA receptor trafficking to the PSD in response to LTP

[edit]

Once AMPA receptors are transported to the perisynaptic region through PKA or SAP97 phosphorylation, receptors are then trafficked to the postsynaptic density (PSD). However, this process of trafficking to the PSD still remains controversial. One possibility is that, during LTP, there is lateral movement of AMPA receptors from perisynaptic sites directly to the PSD.[45] Another possibility is that exocytosis of intracellular vesicles is responsible for AMPA trafficking to the PSD directly.[46] Recent evidence suggests that both of these processes are happening after an LTP stimulus; however, only the lateral movement of AMPA receptors from the perisynaptic region enhances the number of AMPA receptors at the PSD.[47] The exact mechanism responsible for lateral movement of AMPA receptors to the PSD remains to be discovered; however, research has discovered several essential proteins for AMPA receptor trafficking. For example, overexpression of SAP97 leads to increased AMPA receptor trafficking to synapses.[48] In addition to influencing synaptic localization, SAP97 has also been found to influence AMPA receptor conductance in response to glutamate.[49] Myosin proteins are calcium sensitive motor proteins that have also been found to be essential for AMPA receptor trafficking. Disruption of myosin Vb interaction with Rab11 and Rab11-FIP2 blocks spine growth and AMPA receptor trafficking.[50] Therefore, it is possible that myosin may drive the lateral movement of AMPA receptors in the perisynaptic region to the PSD. Transmembrane AMPA receptor regulatory proteins (TARPs) are a family protein that associate with AMPA receptors and control their trafficking and conductance.[51] CACNG2 (Stargazin) is one such protein and is found to bind AMPA receptors in the perisynaptic and postsynaptic regions.[52] The role of stargazin in trafficking between the perisynaptic and postsynaptic regions remains unclear; however, stargazin is essential for immobilizing AMPA receptors in the PSD by interacting with PSD-95.[53] PSD-95 stabilizes AMPA receptors to the synapse and disruption of the stargazin-PSD-95 interaction suppressed synaptic transmission.[15]

Biophysics of AMPA receptor trafficking

[edit]

The movement of AMPA receptors within the neuronal membrane is commonly modeled as Brownian diffusion, reflecting their lateral mobility across the lipid bilayer. However, at synaptic sites— particularly the postsynaptic density (PSD)—this motion is modulated by retention forces that can transiently stabilize receptors.[54][55][56] These forces do not completely immobilize AMPARs but instead permit a dynamic exchange with receptors in the perisynaptic domain.[54][55]

The molecular basis for this stabilization is believed to involve nanodomain organization within the PSD, including anchoring interactions with scaffolding proteins such as PSD-95 and transmembrane AMPA receptor regulatory proteins (TARPs).[57][58] Recent evidence suggests that this compartmentalization may arise through liquid-liquid phase separation (LLPS), a biophysical process by which biomolecular condensates form via weak, multivalent interactions. LLPS may contribute to the formation of synaptic nanodomains that selectively retain or enrich AMPARs at functional sites within the PSD.[57][58]

Constitutive trafficking and changes in subunit composition

[edit]

AMPA receptors are continuously being trafficked (endocytosed, recycled, and reinserted) into and out of the plasma membrane. Recycling endosomes within the dendritic spine contain pools of AMPA receptors for such synaptic reinsertion.[59] Two distinct pathways exist for the trafficking of AMPA receptors: a regulated pathway and a constitutive pathway.[60][61]

In the regulated pathway, GluA1-containing AMPA receptors are trafficked to the synapse in an activity-dependent manner, stimulated by NMDA receptor activation.[17] Under basal conditions, the regulated pathway is essentially inactive, being transiently activated only upon the induction of long-term potentiation.[59][60] This pathway is responsible for synaptic strengthening and the initial formation of new memories.[62]

In the constitutive pathway, GluA1-lacking AMPA receptors, usually GluR2-GluR3 heteromeric receptors, replace the GluA1-containing receptors in a one-for-one, activity-independent manner,[63][64] preserving the total number of AMPA receptors in the synapse.[59][60] This pathway is responsible for the maintenance of new memories, sustaining the transient changes resulting from the regulated pathway. Under basal conditions, this pathway is routinely active, as it is necessary also for the replacement of damaged receptors.

The GluA1 and GluA4 subunits consist of a long carboxy (C)-tail, whereas the GluA2 and GluA3 subunits consist of a short carboxy-tail. The two pathways are governed by interactions between the C termini of the AMPA receptor subunits and synaptic compounds and proteins. Long C-tails prevent GluR1/4 receptors from being inserted directly into the postsynaptic density zone (PSDZ) in the absence of activity, whereas the short C-tails of GluA2/3 receptors allow them to be inserted directly into the PSDZ.[45][65] The GluA2 C terminus interacts with and binds to N-ethylmaleimide sensitive fusion protein (NSF),[66][67][68] which allows for the rapid insertion of GluR2-containing AMPA receptors at the synapse.[69] In addition, GluR2/3 subunits are more stably tethered to the synapse than GluR1 subunits.[70][71][72]

LTD-induced endocytosis of AMPA receptors

[edit]
LTD-Induced AMPA Receptor Endocytosis
LTD-induced endocytosis of AMPA receptors

Long-term depression enacts mechanisms to decrease AMPA receptor density in selected dendritic spines, dependent on clathrin and calcineurin and distinct from that of constitutive AMPAR trafficking. The starting signal for AMPAR endocytosis is an NMDAR-dependent calcium influx from low-frequency stimulation, which in turn activates protein phosphatases PP1 and calcineurin. However, AMPAR endocytosis has also been activated by voltage-dependent calcium channels, agonism of AMPA receptors, and administration of insulin, suggesting general calcium influx as the cause of AMPAR endocytosis.[73] Blockage of PP1 did not prevent AMPAR endocytosis, but antagonist application to calcineurin led to significant inhibition of this process.[74]

Calcineurin interacts with an endocytotic complex at the postsynaptic zone, explaining its effects on LTD.[75] The complex, consisting of a clathrin-coated pit underneath a section of AMPAR-containing plasma membrane and interacting proteins, is the direct mechanism for reduction of AMPARs, in particular GluR2/GluR3 subunit-containing receptors, in the synapse. Interactions from calcineurin activate dynamin GTPase activity, allowing the clathrin pit to excise itself from the cell membrane and become a cytoplasmic vesicle.[76] Once the clathrin coat detaches, other proteins can interact directly with the AMPARs using PDZ carboxyl tail domains; for example, glutamate receptor-interacting protein 1 (GRIP1) has been implicated in intracellular sequestration of AMPARs.[77] Intracellular AMPARs are subsequently sorted for degradation by lysosomes or recycling to the cell membrane.[78] For the latter, PICK1 and PKC can displace GRIP1 to return AMPARs to the surface, reversing the effects of endocytosis and LTD. when appropriate.[79] Nevertheless, the highlighted calcium-dependent, dynamin-mediated mechanism above has been implicated as a key component of LTD. and as such may have applications to further behavioral research.[80]

Role in epileptic seizures

[edit]

AMPA receptors play a key role in the generation and spread of epileptic seizures.[81] Activation of AMPARs by agonists such as kainic acid, a convulsant that is widely used in epilepsy research,[82] has been shown to induce seizures in both animal models and humans, emphasizing their contribution to epileptogenesis. Conversely, antagonists targeting AMPARs have demonstrated efficacy in suppressing seizure activity, highlighting their potential as therapeutic agents in epilepsy management.[83]

Molecular target for epilepsy therapy

[edit]

The noncompetitive AMPA receptor antagonists talampanel and perampanel have been demonstrated to have activity in the treatment of adults with partial-onset seizures,[84][85] indicating that AMPA receptor antagonists represent a potential target for the treatment of epilepsy.[86][87] Perampanel (trade name: Fycompa) received Marketing Authorisation Approval by the European Commission for the treatment of partial epilepsy on July 27, 2012. The drug was approved in the United States by the Food and Drug Administration (FDA) on October 22, 2012. As has been the case for most recently developed AEDs (AntiEpilectic Drugs) including pregabalin, lacosamide and ezogabine, the FDA recommended that perampanel be classified by the Drug Enforcement Administration (DEA) as a scheduled drug. It has been designated as a Schedule 3 controlled substance.

Decanoic acid acts as a non-competitive AMPA receptor antagonist at therapeutically relevant concentrations, in a voltage- and subunit-dependent manner, and this is sufficient to explain its antiseizure effects.[88] This direct inhibition of excitatory neurotransmission by decanoic acid in the brain contributes to the anticonvulsant effect of the medium-chain triglyceride ketogenic diet.[88] Decanoic acid and the AMPA receptor antagonist drug perampanel act at separate sites on the AMPA receptor, and so it is possible that they have a cooperative effect at the AMPA receptor, suggesting that perampanel and the ketogenic diet could be synergistic.[88][89]

Preclinical research suggests that several derivatives of aromatic amino acids with antiglutamatergic properties including AMPA receptor antagonism and inhibition of glutamate release such as 3,5-dibromo-D-tyrosine and 3,5-dibromo-L-phenylalnine exhibit strong anticonvulsant effect in animal models suggesting use of these compounds as a novel class of antiepileptic drugs.[90][91]

AMPA Receptors in Disease Beyond Epilepsy

[edit]

AMPA receptors are essential to excitatory neurotransmission in the CNS.[92] Beyond their established role in epilepsy, recent research indicates that AMPARs are implicated in various neurological and psychiatric disorders, including excitotoxicity in stroke and neurodegeneration, as well as conditions such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Huntington's disease, schizophrenia, and autism spectrum disorders (ASD).[93][94][95][96][97][98]

Excitotoxicity in Stroke and Neurodegeneration

[edit]

Excessive activation of AMPARs, particularly those lacking the GluA2 subunit, leads to increased calcium permeability, contributing to neuronal injury and death—a phenomenon known as excitotoxity. This mechanism in involved in acute events such as stroke and in chronic neurodegenerative diseases.[93] For instance, in ALS, motor neurons exhibit elevated levels of calcium-permeable AMPARs, rendering them more susceptible to excitotoxic damage.[99]

Role in ALS, Alzheimer's, and Huntington's Diseases

[edit]

ALS

[edit]

Motor neurons in ALS patients express high levels of calcium-permeable AMPARs, which, combined with reduced calcium-buffering capacity, make them vulnerable to excitotoxicity.[99]

Alzheimer's Disease

[edit]

Alterations in AMPAR trafficking and function have been observed in Alzheimer's disease models. Dysregulation of the Q/R editing site of the GluA2 subunit affects calcium permeability, influencing dendritic spine morphology and contributing to neurodegeneration and memory deficits.[100]

Huntington's Disease

[edit]

Mutant huntingtin protein disrupts AMPAR-mediated synaptic transmission by impairing receptor trafficking, leading to synaptic dysfunction and neuronal loss in Huntington's disease models.[101]

AMPAR Trafficking Deficits in Schizophrenia and Autism

[edit]

Schizophrenia

[edit]

Abnormal N-linked glycosylation of AMPAR subunits has been reported in schizophrenia, suggesting impaired receptor trafficking and synaptic localization, which may underlie glutamatergic dysfunction observed in the disorder.[102]

Autism Spectrum Disorders (ASD)

[edit]

Alterations in AMPAR trafficking have been implicated in ASD. Studies indicate that dysregulation of proteins involved in AMPAR trafficking, such as CYFIP1, leads to synaptic dysfunction associated with autism-like behaviors.[103]

Agonists

[edit]
Glutamate, the endogenous agonist of the AMPAR.
AMPA, a synthetic agonist of the AMPAR.

Positive allosteric modulators

[edit]
Main article: AMPA receptor positive allosteric modulator

Antagonists

[edit]

Negative allosteric modulators

[edit]
Perampanel, a negative allosteric modulator of the AMPAR used to treat epilepsy.

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

AMPA receptor

View on Grokipedia
from Grokipedia
The AMPA receptor (AMPAR), or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, is a subtype of that mediates the majority of fast excitatory synaptic transmission in the . These receptors function as ligand-gated cation channels, primarily permeable to sodium and ions—and in certain subunit configurations, calcium ions—allowing rapid of postsynaptic neurons upon glutamate binding. AMPARs are tetrameric complexes assembled from four homologous subunits (GluA1–GluA4, encoded by GRIA1–GRIA4 genes), with heteromeric combinations determining their biophysical properties, such as rectification, desensitization kinetics, and calcium permeability. The molecular architecture of AMPARs consists of an extracellular amino-terminal domain for subunit assembly, a bilobed ligand-binding domain that undergoes conformational changes upon glutamate activation, a transmembrane domain forming the central ion-conducting pore, and an intracellular C-terminal tail involved in trafficking and regulatory interactions. Functional diversity is further enhanced by association with auxiliary transmembrane proteins, including TARPs (transmembrane AMPA receptor regulatory proteins) and CNIHs (cornichon homologs), which stabilize the receptor, modulate gating and desensitization, influence synaptic trafficking, and alter pharmacological sensitivity. For instance, GluA2-containing AMPARs typically exhibit low calcium permeability due to a post-transcriptional RNA editing event that replaces a glutamine with arginine (Q/R editing) in the channel pore, introducing a positively charged residue that repels divalent cations such as calcium. Beyond basal transmission, AMPARs are pivotal in , where dynamic insertion, removal, or phosphorylation of receptors at synapses drives (LTP) and long-term depression (LTD), processes fundamental to learning, , and . Dysregulation of AMPAR function contributes to neurological and psychiatric disorders, including , , , and depression, making them key therapeutic targets. Pharmacologically, positive allosteric modulators (e.g., ampakines) enhance receptor activity to boost and , while antagonists mitigate in conditions like and seizures.

Molecular Structure

Subunit Composition

AMPA receptors are tetrameric ligand-gated channels assembled from four homologous subunits known as GluA1 through GluA4, each encoded by distinct genes: GRIA1 for GluA1, GRIA2 for GluA2, GRIA3 for GluA3, and GRIA4 for GluA4. Each subunit comprises approximately 900 and has a molecular weight of around 100 kDa. These subunits share a common modular architecture but exhibit sequence variations that influence receptor properties, such as permeability and gating kinetics. Functional AMPA receptors form as heterotetramers typically composed of two to four distinct subunit types, with GluA2 being the most prevalent subunit in mature neurons, particularly in the hippocampus and cortex. The inclusion of GluA2 renders the receptor calcium-impermeable, a critical feature for preventing excitotoxic damage during synaptic transmission. In adult neurons, nearly all surface AMPA receptors incorporate at least one GluA2 subunit, ensuring low calcium conductance and rectification of current-voltage relationships.00255-4) A key post-transcriptional modification unique to the GluA2 subunit is at the Q/R site, located at residue 607 in the pore-forming 2 (TM2). This editing event, mediated by acting on 2 (ADAR2), converts a genomically encoded (Q) codon to an (R), which blocks calcium permeation through the channel. Inefficient editing at this site results in calcium-permeable receptors, which can lead to neuronal and cell death, as observed in conditions like where ADAR2 activity is compromised. Alternative splicing of AMPA receptor subunit mRNAs generates flip and flop isoforms, differing by a 38- to 49-amino-acid cassette near the of the ligand-binding domain. The flip isoforms exhibit slower desensitization kinetics upon binding compared to flop isoforms, which recover more rapidly but deactivate faster, thereby tuning the temporal profile of synaptic currents. These isoforms are regionally and developmentally regulated; for instance, flop variants predominate in the adult , while flip forms are more common in the developing hippocampus. In vivo, homomeric assemblies of single subunit types are rare and primarily observed in recombinant expression systems or specific developmental stages, whereas heteromeric combinations predominate in native s. Common heteromers include di-heteromers such as GluA1/GluA2, which constitute about 80% of synaptic receptors in hippocampal CA1 pyramidal neurons, and GluA2/GluA3, accounting for much of the remainder.00255-4) Tri- or tetra-heteromers involving GluA4 are less frequent in adults but play roles in early postnatal synapse maturation. The precise influences receptor trafficking, conductance, and plasticity, with GluA2-containing heteromers ensuring the majority of functional receptors at excitatory synapses.

Topology and Quaternary Assembly

The AMPA receptor subunit exhibits a modular transmembrane topology characteristic of ionotropic glutamate receptors. Each subunit comprises an extracellular amino-terminal domain (ATD, also known as NTD), approximately 370 amino acids long, which mediates subunit dimerization; a bilobed ligand-binding domain (LBD) formed by the S1 and S2 segments in a clamshell-like structure for agonist recognition; a transmembrane domain (TMD) consisting of four segments—M1 and M3 as α-helices spanning the membrane, M2 as a re-entrant loop lining the ion-conducting pore, and M4 as a short helix—and an intracellular C-terminal domain (CTD) of 30–50 amino acids that interacts with scaffolding and trafficking proteins. This topology positions the ATD and LBD extracellularly, the TMD embedded in the lipid bilayer, and the CTD cytoplasmically, enabling the receptor's role in synaptic signaling. In its quaternary structure, the functional AMPA receptor assembles as a tetramer, adopting a dimer-of-dimers configuration that imparts overall 2-fold symmetry in the extracellular domains and 4-fold symmetry in the TMD. The two ATD dimers pack the subunits at the top, while the LBDs form two heterodimers or homodimers connected via lobe 1 (D1-D1) contacts, with the TMD linking these layers through the M3 helices that bundle to form the central pore. The overall receptor measures approximately 200 in height from the ATD to the intracellular side and about 140 in width at the LBD layer, creating a chalice-shaped with a large central vestibule. Key interfaces include ATD dimer contacts via conserved residues for initial subunit packing, LBD dimerization stabilized by hydrogen bonds and hydrophobic interactions between D1 lobes, and TMD bundling primarily through M3-M3 contacts that seal the pore in resting states. High-resolution structures determined by cryo-electron microscopy (cryo-EM) have elucidated these features across various states. For instance, the 2014 cryo-EM structure of homomeric GluA2 in apo (resting, 4.4 Å), agonist-bound (3.8 Å), and desensitized (7.5 Å) conformations revealed the static and subtle rearrangements at interfaces, while subsequent 2019 cryo-EM analyses of native heteromeric complexes at ~3.5 Å resolution confirmed non-stochastic subunit arrangements (e.g., GluA2 in specific positions) and the prevalence of triheteromers . Tetrameric assembly initiates in the (ER), where chaperone proteins facilitate proper folding and oligomerization to ensure ER export. Transmembrane AMPA receptor regulatory proteins (TARPs), such as stargazin (γ2), form early complexes with nascent subunits in the ER, promoting tetramerization and maturation by stabilizing the TMD and aiding LBD dimer formation. Additionally, PICK1 interacts with the GluA2 CTD in the ER to regulate assembly and export, preventing premature trafficking of incomplete oligomers. These chaperones ensure only functional tetramers proceed to the Golgi and plasma membrane.

Biophysical Mechanisms

Agonist Binding and Channel Gating

The binding site of the AMPA receptor is situated within the bilobed ligand-binding domain (LBD), composed of the S1 and S2 segments from each subunit, where the glutamate binds between the upper D1 lobe and lower D2 lobe. Upon binding, the LBD undergoes a clamshell-like closure of approximately 26°, which stabilizes the active conformation and initiates downstream conformational changes necessary for channel activation. This closure is more pronounced with full agonists like glutamate compared to partial agonists, reflecting differences in binding . The gating mechanism couples LBD closure to the opening of the pore in the through a series of linker regions connecting the LBD to the membrane-spanning helices. Specifically, the closure of the LBD dimers pulls on the S2-M3 linkers, causing a kink in the M3 helices (particularly at 618) in two opposing subunits, which dilates the pore diameter by about 10 and permits flow. Full requires the binding of two molecules per LBD dimer, as the tetrameric receptor's gating is coordinated across these dimeric units, with subunit influencing the overall efficiency but not fundamentally altering the per-dimer requirement. The kinetics of activation are extremely rapid, with a ranging from 0.1 to 1 ms, enabling the receptor to mediate fast synaptic transmission. For receptors containing the GluA2 subunit, the single-channel conductance is approximately 10 pS under physiological conditions, reflecting the low unitary current typical of calcium-impermeable AMPA receptors. Partial agonists such as kainate or bind to the same LBD site but induce less complete clamshell closure, resulting in lower and submaximal channel opening with reduced peak currents compared to glutamate. Allosteric modulation further refines gating; the N-terminal domain (NTD) influences agonist binding affinity through intersubunit interactions that can alter LBD accessibility, while the C-terminal tails modulate gating kinetics via intracellular protein interactions, such as phosphorylation-dependent associations with proteins.

Desensitization and Recovery

Desensitization of AMPA receptors represents a rapid inactivation mechanism that limits the duration of channel opening following , typically occurring within approximately 10 ms. This process involves conformational rearrangements in the -binding domain (LBD), where binding induces separation of the bilobed LBD structure, uncoupling it from the transmembrane pore and leading to channel closure despite persistent ligand occupancy. Flop isoforms of AMPA receptor subunits desensitize faster than their flip counterparts, with time constants often under 5 ms for flop variants compared to 10-20 ms for flip, due to sequence differences in the C-terminal region of the LBD that stabilize the desensitized state more readily. The structural basis of desensitization has been elucidated through cryo-electron microscopy studies, revealing that in the desensitized conformation, adjacent LBD dimers separate by up to 20 Å, disrupting intersubunit interactions and allowing the M3 transmembrane helices to rearrange and constrict the ion-conducting pore. This lobe separation in the LBD effectively isolates the agonist-bound domain from the gate-forming regions, ensuring efficient inactivation without agonist dissociation. Recovery from the desensitized state occurs with time constants ranging from 10 to 100 ms, depending on the subunit composition and agonist affinity, and is governed primarily by agonist unbinding from the LBD, which permits the receptor to return to a responsive conformation. Transmembrane AMPA receptor regulatory proteins (TARPs), such as γ-2 and γ-8, modulate these kinetics by stabilizing the LBD layer and reducing the propensity for desensitization, thereby slowing entry into the desensitized state by 2- to 5-fold and extending recovery in some complexes. Physiologically, desensitization prevents neuronal overstimulation by curtailing excitatory currents during prolonged glutamate exposure, thereby maintaining synaptic fidelity and . The flip/flop isoform ratio is developmentally regulated, shifting toward a higher proportion of flip variants in adult neurons, which exhibit slower desensitization and support more sustained postsynaptic responses essential for mature circuit function. Mutations impairing desensitization, such as the Lurcher mutation in the GluA2 subunit that disrupts LBD-pore coupling, lead to excessive channel activity and are associated with severe and cognitive deficits in animal models, underscoring the therapeutic potential of targeting desensitization to mitigate hyperexcitability in such disorders.

Ion Permeability and Conductance

AMPA receptors function as non-selective cation channels that are primarily permeable to sodium (Na⁺) and potassium (K⁺) ions, resulting in a reversal potential close to 0 mV under physiological conditions. The inclusion of the GluA2 subunit, especially when RNA-edited at the Q/R site to arginine (R), typically reduces calcium (Ca²⁺) permeability to very low levels (<1% of the total ionic current in most cases), though recent studies indicate a continuum of permeabilities depending on receptor configuration, effectively limiting significant Ca²⁺ entry and protecting neurons from excitotoxic damage in typical scenarios. In contrast, AMPA receptors lacking GluA2 or containing unedited GluA2 (with glutamine, Q, at the Q/R site) exhibit high Ca²⁺ permeability, with a relative permeability ratio P_Ca/P_Na approaching 1–1.5. The selectivity for ions is determined by the M2 loop in the channel pore, where the critical Q/R site acts as a selectivity filter: the unedited allows permeation of divalent cations like Ca²⁺, while the edited introduces a positive charge that repels them, favoring monovalent flow. Unedited GluA2 homomeric receptors are highly Ca²⁺-permeable and display single-channel conductances of approximately 20-25 pS, reflecting their distinct biophysical profile compared to edited heteromers. AMPA receptors lacking GluA2 exhibit inward rectification, characterized by larger currents at negative potentials and reduced currents at positive potentials, due to voltage-dependent block by endogenous intracellular polyamines such as spermine. This block is relieved at hyperpolarized potentials, allowing enhanced Na⁺ influx during synaptic activation. The current-voltage relationship can be approximated by a model of open-channel block:
I=g⋅(V−Erev)/(1+[polyamine]iKd(V))I = g \cdot (V - E_{\text{rev}}) / \left(1 + \frac{[\text{polyamine}]_i}{K_d(V)}\right)
where gg is the single-channel conductance, ErevE_{\text{rev}} is the reversal potential (~0 mV), [polyamine]i[\text{polyamine}]_i is the intracellular polyamine concentration, and Kd(V)K_d(V) is the voltage-dependent dissociation constant for the blocker. Auxiliary subunits such as transmembrane AMPA receptor regulatory proteins (TARPs), exemplified by stargazin (γ2), enhance channel conductance by 2–3 fold, shifting main conductance levels from ~8 pS to ~20 pS, and modestly reduce block, thereby slightly increasing effective Ca²⁺ permeability in some configurations. During neural development, immature synapses often display higher Ca²⁺ permeability owing to lower expression of GluA2 subunits, facilitating Ca²⁺-dependent signaling for and plasticity, which matures into predominantly GluA2-containing receptors with low Ca²⁺ permeability.

Physiological Functions

Role in Fast Synaptic Transmission

AMPA receptors are predominantly localized at postsynaptic sites within neuronal dendrites, where they form the primary mediators of excitatory synaptic transmission in the . These receptors are present at the majority of excitatory synapses (typically over 90% in adult brain regions), enabling rapid signal propagation between neurons. Upon presynaptic release of glutamate from a , receptors rapidly activate, generating fast excitatory postsynaptic currents (EPSCs) with a of less than 1 ms and a decay time of 5-10 ms. These -mediated EPSCs account for about 90% of the excitatory synaptic drive in the , ensuring efficient temporal in neural communication. Desensitization of receptors helps limit responses to prolonged glutamate exposure, maintaining the precision of brief synaptic events. The depolarizing currents produced by AMPA receptor activation play a crucial role in synaptic integration by relieving the voltage-dependent magnesium (Mg²⁺) block of NMDA receptors, thereby facilitating their subsequent activation and contributing to mechanisms like and depression. A minor population of extrasynaptic AMPA receptors contributes to tonic currents arising from ambient glutamate or volume transmission, modulating baseline neuronal excitability outside of precise synaptic cleft signaling. In quantitative terms, the release of a single in the hippocampus typically activates approximately 5-20 AMPA receptors, resulting in an (EPSP) amplitude of approximately 0.5 mV, which underscores the high efficiency of these receptors in driving postsynaptic responses. Recent studies (as of 2025) further emphasize AMPA receptors' role in fine-tuning circuit-specific transmission for adaptive neural processing.

Involvement in Synaptic Plasticity

The involvement of receptors in centers on their dynamic trafficking to and from the postsynaptic membrane, which underlies (LTP) and long-term depression (LTD). In LTP, calcium influx through NMDA receptors activates calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates the GluA1 subunit at serine 831 (Ser831), promoting the insertion of GluA1-containing receptors into the postsynaptic density (PSD). This process increases synaptic receptor content by approximately 2- to 3-fold, enhancing excitatory transmission. (PKA) also contributes by phosphorylating GluA1 at serine 845 (Ser845), facilitating receptor and surface stabilization during LTP induction. In contrast, LTD involves the removal of receptors from the through , triggered by lower levels of NMDA receptor-mediated calcium influx that activate and protein phosphatase 1 (PP1). These phosphatases dephosphorylate GluA1 at Ser845, destabilizing surface receptors and promoting their internalization via clathrin- and AP2 adaptor protein-dependent , which reduces surface receptor levels by about 50%. This is subunit-specific, with GluA2-containing receptors preferentially targeted for removal during LTD. AMPA receptor trafficking occurs through constitutive cycling, where receptors undergo and recycling every 10–30 minutes under basal conditions, maintaining synaptic . Activity-dependent regulation involves Rab GTPases, such as Rab8 for facilitating receptor insertion during LTP and Rab5 for enhancing in LTD. GluA1 subunits drive LTP by enabling preferential insertion of homomeric or GluA1/GluA2 heteromeric receptors, while GluA2 mediates LTD through its role in ; this dynamic allows the conversion of silent synapses—those containing only NMDA receptors—into functional AMPA receptor-containing synapses via LTP. Biophysically, LTP not only increases receptor number but also enhances single-channel conductance and open probability of AMPA receptors through Ser831 , amplifying postsynaptic responses. Conversely, LTD decreases quantal size by reducing the number of functional synaptic AMPA receptors without altering intrinsic channel properties. These changes in AMPA receptor dynamics are essential for experience-dependent modifications in synaptic strength, supporting learning and processes.

Pathological Roles

Contribution to Epilepsy

AMPA receptor hyperactivity plays a central role in the hyperexcitability underlying , particularly in (TLE), where increased AMPA-mediated currents arise from upregulated expression of GluA1 and GluA3 subunits or impaired desensitization mechanisms. In TLE models and patient tissues, this upregulation enhances synaptic excitatory transmission, promoting recurrent seizures. Additionally, calcium-permeable AMPA receptors (CP-AMPARs), formed by unedited GluA2 subunits lacking the Q/R site editing (resulting in a at position 607), allow excessive Ca²⁺ influx that exacerbates excitotoxic neuronal death during prolonged seizures. Genetic mutations in AMPA receptor genes further link these receptors to . Variants in GRIA1 and GRIA2, such as those disrupting GluA2 editing at codon 607, lead to CP-AMPARs and are associated with familial epilepsy syndromes, often accompanied by . Gain-of-function mutations in GRIA3, encoding GluA3, have been implicated in myoclonic epilepsies, including cases of myoclonic , by enhancing receptor activity and network excitability. In propagation, receptors drive the initial of neuronal networks, facilitating the spread of epileptiform activity across regions. Preclinical models demonstrate that AMPA receptor antagonists, such as NBQX, significantly reduce severity by blocking this excitatory drive, highlighting the receptors' role in synchronizing pathological discharges. Therapeutically, AMPA receptors are targeted with non-competitive antagonists like , approved in 2012, which selectively block receptors in open or desensitized states to suppress hyperexcitability without affecting NMDA receptors. In contrast, positive allosteric modulators of AMPA receptors are avoided in epilepsy treatment due to their potential to enhance currents and provoke seizures. Clinically, AMPA antagonists serve as adjunctive therapies for refractory , with reducing frequency by 20-50% in patients with partial-onset seizures unresponsive to other antiepileptics. This efficacy is evident in randomized trials, where 8-12 mg doses achieved ≥50% responder rates in up to 30% of cases, improving outcomes in drug-resistant populations.

Implications in Neurodegenerative Diseases

AMPA receptors contribute to excitotoxic damage in neurodegenerative diseases primarily through mechanisms involving calcium-permeable channels. Excessive glutamate release activates AMPA receptors, particularly those lacking the edited GluA2 subunit, leading to sustained Ca²⁺ influx that overwhelms cellular . This influx activates catabolic enzymes, generates , and induces mitochondrial permeability transition, culminating in the release of proapoptotic factors like and subsequent neuronal . In ischemic conditions such as , reduced GluA2 —mediated by downregulation of acting on 2 (ADAR2)—further enhances Ca²⁺ permeability, amplifying vulnerability to neurodegeneration. In , AMPA receptor-mediated drives infarct expansion following cerebral ischemia. AMPA antagonists, such as talampanel, have demonstrated robust in models of transient and permanent focal ischemia. For instance, talampanel administration reduced cortical infarct size by 47-48% in rats, even when initiated up to 2 hours post-occlusion, while also preserving neurological function in behavioral assays like rotarod and beam walking tests. These findings underscore the therapeutic window for targeting AMPA receptors in acute ischemic events. Amyotrophic lateral sclerosis (ALS) features AMPA receptor dysregulation that promotes degeneration via enhanced . Reduced GluA2 subunit expression in sporadic ALS post-mortem tissue results in a higher proportion of Ca²⁺-permeable AMPA receptors, facilitating excessive Ca²⁺ entry and accelerating ; similar patterns occur in genetic forms like C9orf72-related ALS, with elevated GluA1 levels. Dysregulation of transmembrane AMPA receptor regulatory proteins (TARPs), which modulate receptor trafficking and gating, further increases Ca²⁺ permeability in affected neurons. , a disease-modifying for ALS, indirectly modulates AMPA receptors by enhancing surface expression of GluA1 and GluA2 subunits while attenuating transmission efficacy, thereby mitigating excitotoxic burden. In , amyloid-β (Aβ) oligomers disrupt AMPA receptor dynamics, impairing and . Aβ promotes rapid of surface AMPA receptors through NMDA receptor-dependent of GluA1 at Ser-845 and 5-mediated ubiquitination, reducing synaptic GluA1 and GluA2 content. This favors long-term depression-like mechanisms over potentiation, blocking (LTP) induction in hippocampal slices and correlating with deficits in tasks. GluA1 trafficking impairments, in particular, link these changes to early memory loss, as synaptic AMPA receptor loss precedes overt neuronal death. Huntington's disease involves mutant huntingtin-mediated alterations in AMPA receptor localization that exacerbate synaptic dysfunction. The polyglutamine-expanded protein impairs anterograde transport and surface expression of GluA2-containing AMPA receptors, shifting toward Ca²⁺-permeable compositions and promoting loss in striatal medium spiny neurons. This dysregulation contributes to early synaptic weakening and motor deficits in transgenic models. AMPA receptor antagonists, by stabilizing receptor and reducing excitotoxic signaling, have slowed disease progression in these models, improving and behavioral outcomes. Across these disorders, Ca²⁺-permeable AMPA receptors emerge as a convergent therapeutic target to curb . Strategies to restore GluA2 Q/R site editing, such as ADAR2 or upregulation, have shown promise in preclinical models by normalizing receptor permeability and preventing loss; similar approaches are proposed for ischemia and other conditions to mitigate downstream apoptotic cascades.

Associations with Neuropsychiatric Disorders

Dysregulation of AMPA receptors has been implicated in , with reduced expression of the GluA1 subunit in the contributing to impaired (LTP) and cognitive deficits. Postmortem studies reveal decreased GluA1 mRNA and protein levels in the and hippocampus of individuals with , supporting a role for hypofunction in the disorder. Genetic variants in the GRIA1 gene, which encodes GluA1, have been associated with increased risk, as evidenced by genome-wide association studies identifying loci near GRIA1 and case-control analyses linking specific polymorphisms to susceptibility. This AMPA receptor hypofunction is thought to disrupt the depolarization required for optimal activation, leading to broader excitatory-inhibitory imbalances characteristic of . In autism spectrum disorders (ASD), mutations in GRIA3 and GRIA4 genes, encoding GluA3 and GluA4 subunits, are linked to syndromic forms of the condition, often presenting with and seizures. For instance, de novo heterozygous variants in GRIA4, such as those affecting the channel pore or subunit assembly, result in altered receptor function and neurodevelopmental phenotypes including impairments. Similarly, loss-of-function mutations in GRIA3 cause X-linked combined with autism features, while gain-of-function variants lead to early-onset seizures and . These genetic alterations disrupt AMPA receptor trafficking, reducing synaptic surface expression and impairing excitatory transmission critical for circuits. Shared deficits across and ASD involve excessive endocytosis, often mediated by disrupted interactions with postsynaptic density protein 95 (PSD-95), which normally stabilizes receptors at synapses. This leads to diminished synaptic strength and altered excitation-inhibition balance, contributing to cognitive and behavioral symptoms. Animal models, such as GluA1 knockout mice, recapitulate schizophrenia-like behaviors including impaired , novelty-induced hyperlocomotion, and social deficits, alongside reduced hippocampal . The hypofunction hypothesis posits that glutamate system imbalances underlie these disorders, with therapeutic potential in positive allosteric modulators to restore transmission. For example, LY451646 enhances in preclinical models of and depression by promoting BDNF expression and , and early clinical trials in showed mixed but promising effects on cognitive measures, suggesting applicability to neuropsychiatric conditions. Postmortem evidence supports AMPA hypofunction, with systematic reviews indicating decreased receptor binding or subunit expression in the hippocampus of patients in approximately 75% of studies, and disruptions in AMPA-mediated transmission observed in ASD models. In ASD rodent models with GluA2 knockdown, such as those mimicking SHANK3 deficiency, repetitive behaviors emerge alongside reduced synaptic AMPA currents, highlighting conserved mechanisms amenable to modulation.

Pharmacology

Agonists and Partial Agonists

The primary endogenous of AMPA receptors is L-glutamate, which binds to the ligand-binding domain (LBD) with full efficacy and an value of approximately 300–500 μM, depending on the subunit composition and experimental conditions. Synthetic full agonists include α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (), which activates AMPA receptors with high potency ( ≈ 5–10 μM) and is widely used as a selective tool compound. Quisqualate, another synthetic full agonist, exhibits even higher potency ( ≈ 1–20 μM) but lacks selectivity, as it also activates metabotropic glutamate receptors and other ionotropic subtypes. Partial agonists of receptors, which elicit submaximal responses, include kainate with an of approximately 500 μM and efficacy of 50–70% relative to glutamate, reflecting its ability to induce partial closure of the LBD. Derivatives of willardiine, such as (S)-fluorowillardiine, act as potent partial agonists ( ≈ 1.5 μM) with subtype selectivity favoring GluA3- and GluA4-containing receptors, making them valuable for probing specific receptor populations. AMPA receptor agonists bind within the bilobed LBD, stabilizing the closed-cleft conformation that promotes channel opening and ion flux. For most subunit combinations, the potency order follows > L-glutamate, as evidenced by lower values for AMPA in recombinant and native systems. These compounds serve primarily as research tools in to study receptor kinetics, synaptic transmission, and plasticity, but no AMPA receptor agonists have reached clinical use due to risks of , seizures, and neuronal damage from excessive activation.

Antagonists and Negative Allosteric Modulators

Competitive antagonists of AMPA receptors bind to the ligand-binding domain (LBD), preventing activation. A prototypical example is 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), which exhibits an of approximately 0.3 μM for AMPA receptors and also inhibits kainate receptors with lower potency ( ~1.5 μM). NBQX, a more selective derivative, displays higher potency against AMPA receptors ( ~0.15 μM) with over 5000-fold selectivity over kainate receptors, making it a preferred tool for isolating AMPA-mediated responses. Non-competitive antagonists, such as the GYKI-52466 series of 2,3-benzodiazepines, bind to the and block the open channel pore in a use-dependent manner, with IC50 values around 10-20 μM for receptor-mediated currents. , a structurally distinct aryl-substituted 2-pyridone, functions similarly as a non-competitive with an IC50 of approximately 0.1 μM for -induced calcium influx and was approved by the FDA in 2012 as an adjunctive therapy for partial-onset seizures in patients aged 12 and older. Negative allosteric modulators (NAMs) reduce receptor efficacy by stabilizing desensitized states without directly occluding the channel. CP-465,022 exemplifies this class, acting as a potent NAM with an of 25 nM that selectively inhibits responses while weakly affecting NMDA, GABA, and kainate receptors. Unlike positive allosteric modulators that enhance desensitization recovery, true NAMs like CP-465,022 diminish peak currents and accelerate desensitization onset. Selectivity among antagonists varies by subunit composition; for instance, philanthotoxin-74 preferentially blocks calcium-permeable AMPA receptors lacking the GluA2 subunit ( ~0.3 μM for GluA1 and GluA3 homomers), with reduced potency on GluA2-containing receptors due to the residue at the Q/R site. Clinically, AMPA antagonists like offer in models of ischemia and by limiting excitotoxic glutamate signaling, though high doses often induce side effects such as and . Preclinical studies of competitive antagonists like ZK200775 showed promise in reducing infarct volume for , but early clinical trials were limited by significant sedative effects and motor impairments, precluding further development.

Positive Allosteric Modulators

Positive allosteric modulators (PAMs) of AMPA receptors enhance receptor function by binding to allosteric sites distinct from the orthosteric -binding pocket, primarily at the dimer interface of the ligand-binding domains (LBDs) or within the transmembrane region. These binding events stabilize the active conformation of the LBD dimers, thereby slowing the rate of receptor desensitization and prolonging channel opening in the presence of agonists like glutamate. This mechanism results in amplified peak current responses, typically increasing them by 2- to 10-fold, without activating the receptor in the absence of an agonist. Key examples of AMPA receptor PAMs include cyclothiazide (CTZ), a benzothiadiazide that potently inhibits desensitization by binding at the LBD dimer interface. CTZ slows recovery from desensitization by more than 100-fold and exhibits an EC50 of approximately 1 μM for potentiation of glutamate-evoked currents. Another early example is , a pyrrolidone-based that enhances AMPA receptor-mediated responses with an EC50 of around 100 μM and readily crosses the blood-brain barrier due to its lipophilic properties. Subtype selectivity varies among PAMs; for instance, certain compounds preferentially potentiate receptors containing GluA1 and GluA2 subunits, influencing their efficacy in specific neuronal contexts. LY451395 (also known as mibampator), a biarylpropylsulfonamide derivative, demonstrates such selectivity and has been shown to enhance (LTP) in preclinical models by augmenting AMPA receptor currents. This compound advanced to clinical trials for , where it was tested for potential benefits in cognitive deficits and agitation, though it did not significantly improve core symptoms. Structural studies reveal that PAMs like CTZ occupy a solvent-accessible at the LBD dimer interface, promoting tighter D1-D1 lobe interactions and preventing the conformational shifts that lead to desensitization. Critically, these modulators do not induce agonist-independent channel opening, ensuring their effects are contingent on endogenous glutamate release and minimizing off-target . Therapeutically, AMPA PAMs are explored as nootropics to boost by facilitating processes like LTP. In clinical development, compounds such as PF-04958242 (also known as BIIB104), a potent PAM, entered Phase II trials in the 2020s for and negative symptoms in but was discontinued following negative results in the TALLY study, despite showing tolerability. More recently, osavampator (NBI-1065845), a selective AMPA PAM, demonstrated positive results in a Phase 2 trial for as of September 2025. Similar agents are under investigation for depression, leveraging their ability to enhance signaling in mood-regulating circuits.

References

  1. https://www.sciencedirect.com/topics/neuroscience/ampa-receptor
  2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8842481/
  3. https://www.sciencedirect.com/science/article/pii/S0896627317303021
  4. https://www.science.org/doi/10.1126/science.aaw8250
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC7392800/
  6. https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2025.1661342/full
  7. https://www.pnas.org/doi/10.1073/pnas.2425172122
  8. https://pmc.ncbi.nlm.nih.gov/articles/PMC11754374/
  9. https://www.sciencedirect.com/science/article/pii/S1876162315000759
  10. https://pubmed.ncbi.nlm.nih.gov/21426207/
  11. https://elifesciences.org/articles/80950
  12. https://www.sciencedirect.com/topics/[neuroscience](/page/Neuroscience)/ampa-receptor
  13. https://pmc.ncbi.nlm.nih.gov/articles/PMC6214363/
  14. https://www.jneurosci.org/content/17/24/9393
  15. https://pmc.ncbi.nlm.nih.gov/articles/PMC3324117/
  16. https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-0545-1
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC6674648/
  18. https://www.jneurosci.org/content/20/6/2166
  19. https://pubs.acs.org/doi/abs/10.1021/bi8015907
  20. https://www.nature.com/articles/s41467-019-12096-7
  21. https://pmc.ncbi.nlm.nih.gov/articles/PMC2992128/
  22. https://www.cell.com/cell/fulltext/S0092-8674(14)00937-4
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC4293052/
  24. https://www.sciencedirect.com/science/article/pii/S0896627304000182
  25. https://journals.physiology.org/doi/full/10.1152/physiologyonline.2000.15.2.83
  26. https://www.jneurosci.org/content/30/12/4449
  27. https://www.jneurosci.org/content/17/1/58
  28. https://www.nature.com/articles/s41586-025-08736-2
  29. https://www.sciencedirect.com/science/article/pii/0896627395900497
  30. https://www.jneurosci.org/content/34/35/11673
  31. https://pmc.ncbi.nlm.nih.gov/articles/PMC5056834/
  32. https://www.jneurosci.org/content/20/21/7922
  33. https://pmc.ncbi.nlm.nih.gov/articles/PMC10479373/
  34. https://pmc.ncbi.nlm.nih.gov/articles/PMC7175813/
  35. https://pmc.ncbi.nlm.nih.gov/articles/PMC11421597/
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC5370185/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC1300430/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC4195488/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC3079375/
  40. https://pmc.ncbi.nlm.nih.gov/articles/PMC6730404/
  41. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130924
  42. https://link.springer.com/article/10.1007/s10571-024-01529-7
  43. https://www.science.org/doi/10.1126/science.276.5321.2042
  44. https://www.annualreviews.org/doi/10.1146/annurev.neuro.25.112701.142758
  45. https://pubmed.ncbi.nlm.nih.gov/12536214/
  46. https://www.jneurosci.org/content/32/43/15036
  47. https://pmc.ncbi.nlm.nih.gov/articles/PMC6748377/
  48. https://www.sciencedirect.com/science/article/abs/pii/S0306452216300896
  49. https://pmc.ncbi.nlm.nih.gov/articles/PMC4742248/
  50. https://www.frontiersin.org/journals/synaptic-neuroscience/articles/10.3389/fnsyn.2020.00026/full
  51. https://www.frontiersin.org/journals/neural-circuits/articles/10.3389/fncir.2021.711564/full
  52. https://pmc.ncbi.nlm.nih.gov/articles/PMC3351098/
  53. https://www.nature.com/articles/s41467-019-10910-w
  54. https://pmc.ncbi.nlm.nih.gov/articles/PMC10754216/
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC8782781/
  56. https://pmc.ncbi.nlm.nih.gov/articles/PMC11068105/
  57. https://pmc.ncbi.nlm.nih.gov/articles/PMC4506648/
  58. https://www.dovepress.com/the-ampa-receptor-as-a-therapeutic-target-in-epilepsy-preclinical-and--peer-reviewed-fulltext-article-JRLCR
  59. https://www.jneurosci.org/content/28/32/7979
  60. https://www.eisai.com/news/news201274.html
  61. https://www.sciencedirect.com/science/article/abs/pii/S0197018612000964
  62. https://pmc.ncbi.nlm.nih.gov/articles/PMC3784051/
  63. https://www.neurology.org/doi/10.1212/WNL.0000000000001558
  64. https://pmc.ncbi.nlm.nih.gov/articles/PMC3413761/
  65. https://pmc.ncbi.nlm.nih.gov/articles/PMC4002277/
  66. https://pubmed.ncbi.nlm.nih.gov/15925143/
  67. https://www.sciencedirect.com/science/article/abs/pii/S0361923005003631
  68. https://pmc.ncbi.nlm.nih.gov/articles/PMC6973025/
  69. https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP279029
  70. https://pubmed.ncbi.nlm.nih.gov/15378511/
  71. https://pmc.ncbi.nlm.nih.gov/articles/PMC4814684/
  72. https://www.pnas.org/doi/10.1073/pnas.1614249113
  73. https://pubmed.ncbi.nlm.nih.gov/34681616/
  74. https://pmc.ncbi.nlm.nih.gov/articles/PMC1518651/
  75. https://pmc.ncbi.nlm.nih.gov/articles/PMC2964903/
  76. https://pubmed.ncbi.nlm.nih.gov/2682343/
  77. https://www.sciencedirect.com/topics/medicine-and-dentistry/quisqualic-acid
  78. https://www.cell.com/neuron/fulltext/S0896-6273%2800%2900094-5
  79. https://pmc.ncbi.nlm.nih.gov/articles/PMC3159507/
  80. https://www.jneurosci.org/content/12/2/595
  81. https://www.sciencedirect.com/topics/pharmacology-toxicology-and-pharmaceutical-science/ampa-receptor-agonist
  82. https://pmc.ncbi.nlm.nih.gov/articles/PMC9856200/
  83. https://www.jneurosci.org/content/16/1/200
  84. https://www.caymanchem.com/product/14618/cnqx
  85. https://www.tocris.com/products/nbqx_0373
  86. https://www.sciencedirect.com/science/article/abs/pii/001429999290033Z
  87. https://pubmed.ncbi.nlm.nih.gov/7678966/
  88. https://www.tocris.com/products/gyki-52466-dihydrochloride_1454
  89. https://aesnet.org/abstractslisting/blocking-mechanism-of-the-ampa-receptor-antagonist-perampanel
  90. https://hellobio.com/cp-465022-hydrochloride.html
  91. https://pubmed.ncbi.nlm.nih.gov/18378265/
  92. https://www.tocris.com/products/philanthotoxin-74_2770
  93. https://www.jneurosci.org/content/31/14/5378
  94. https://pmc.ncbi.nlm.nih.gov/articles/PMC12562446/
  95. https://www.sciencedirect.com/topics/medicine-and-dentistry/ampa-receptor-antagonist
  96. https://pubmed.ncbi.nlm.nih.gov/16131799/
  97. https://pmc.ncbi.nlm.nih.gov/articles/PMC4107126/
  98. https://www.nature.com/articles/s41594-024-01328-0
  99. https://www.mdpi.com/1422-0067/26/13/6450
  100. https://pmc.ncbi.nlm.nih.gov/articles/PMC3792577/
  101. https://books.rsc.org/books/edited-volume/976/chapter/775534/AMPA-Receptor-Positive-Allosteric-Modulators-a
  102. https://pmc.ncbi.nlm.nih.gov/articles/PMC9585480/
  103. https://www.researchgate.net/publication/6418811_AMPA_potentiator_treatment_of_cognitive_deficits_in_Alzheimer_disease
  104. https://synapse.patsnap.com/drug/d42fd0b5196b4e66a0013c19af32a5e7
  105. https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-presents-positive-new-data-phase-2-study
Add your contribution
Related Hubs
User Avatar
No comments yet.