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The Journal of Physiology Jan 2021
Topics: Ion Channels; Neurotransmitter Agents; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate
PubMed: 33448020
DOI: 10.1113/JP280800 -
Neuropharmacology Aug 2021Exquisitely-regulated synaptic transmission and plasticity underlie higher brain functions such as learning and memory. PSD-95, a member of the MAGUK family, scaffolds... (Review)
Review
Exquisitely-regulated synaptic transmission and plasticity underlie higher brain functions such as learning and memory. PSD-95, a member of the MAGUK family, scaffolds an array of postsynaptic proteins including AMPA and NMDA receptors, and plays essential roles in excitatory synaptic transmission and postsynaptic organization. Epilepsy-related secreted protein LGI1 and its receptor ADAM22 represent major constituent elements of the PSD-95-containing synaptic protein complex in the brain. Recent studies begin to reveal a trans-synaptic configuration of the LGI1-ADAM22 complex and its pivotal role in AMPA and NMDA receptor-mediated synaptic transmission through regulating MAGUKs. Especially interesting is that without the association with LGI1-ADAM22, PSD-95 cannot potentiate AMPA receptor-mediated synaptic transmission. Here, we review roles of LGI1-ADAM22 in synaptic function, and discuss its modes of action on the MAGUK regulation: as (i) a trans-synaptic hub, (ii) an extracellular scaffold, and (iii) an allosteric activator. We also highlight patho-physiological roles of the LGI1-ADAM22-MAGUK linkage in synaptic disorders such as epilepsy and autoimmune limbic encephalitis.
Topics: ADAM Proteins; Animals; Brain; Epilepsy; Guanylate Kinases; Humans; Intracellular Signaling Peptides and Proteins; Nerve Tissue Proteins; Receptors, AMPA; Receptors, N-Methyl-D-Aspartate; Synapses; Synaptic Transmission
PubMed: 34089731
DOI: 10.1016/j.neuropharm.2021.108628 -
Small GTPases Nov 2019Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is... (Review)
Review
Synaptic connections in the brain are continuously weakened or strengthened in response to changes in neuronal activity. This process, known as synaptic plasticity, is the cellular basis for learning and memory, and is thought to be altered in several neuronal disorders. An important aspect of synaptic plasticity is the tightly controlled trafficking and synaptic targeting of the AMPA-type glutamate receptors, which are the major mediators of fast excitatory transmission in the brain. This review addresses the role of Rab GTPases in AMPA receptor trafficking in neurons under basal conditions and during activity-induced synaptic plasticity, especially during long-term potentiation (LTP) and long-term depression (LTD). We highlight the importance of the tight spatio-temporal control of Rab activity and suggest that this is critical for proper neuronal functions. We also discuss how abnormal AMPA receptor trafficking and malfunctioning of Rabs can lead to neurologic disorders or memory problems.
Topics: Animals; Neuronal Plasticity; Neurons; Protein Transport; Receptors, AMPA; rab GTP-Binding Proteins
PubMed: 28628388
DOI: 10.1080/21541248.2017.1337546 -
International Journal of Molecular... Dec 2023Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory... (Review)
Review
Synaptic plasticity enhances or reduces connections between neurons, affecting learning and memory. Postsynaptic AMPARs mediate greater than 90% of the rapid excitatory synaptic transmission in glutamatergic neurons. The number and subunit composition of AMPARs are fundamental to synaptic plasticity and the formation of entire neural networks. Accordingly, the insertion and functionalization of AMPARs at the postsynaptic membrane have become a core issue related to neural circuit formation and information processing in the central nervous system. In this review, we summarize current knowledge regarding the related mechanisms of AMPAR expression and trafficking. The proteins related to AMPAR trafficking are discussed in detail, including vesicle-related proteins, cytoskeletal proteins, synaptic proteins, and protein kinases. Furthermore, significant emphasis was placed on the pivotal role of the actin cytoskeleton, which spans throughout the entire transport process in AMPAR transport, indicating that the actin cytoskeleton may serve as a fundamental basis for AMPAR trafficking. Additionally, we summarize the proteases involved in AMPAR post-translational modifications. Moreover, we provide an overview of AMPAR transport and localization to the postsynaptic membrane. Understanding the assembly, trafficking, and dynamic synaptic expression mechanisms of AMPAR may provide valuable insights into the cognitive decline associated with neurodegenerative diseases.
Topics: Receptors, AMPA; Central Nervous System; Neurons; Cognition; Learning; Central Nervous System Depressants
PubMed: 38203282
DOI: 10.3390/ijms25010111 -
Frontiers in Neural Circuits 2020Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate... (Review)
Review
Excitatory synapses in the mammalian cortex are highly diverse, both in terms of their structure and function. However, relationships between synaptic features indicate they are highly coordinated entities. Imaging techniques, that enable physiology at the resolution of individual synapses to be investigated, have allowed the presynaptic activity level of the synapse to be related to postsynaptic function. This approach has revealed that neuronal activity induces the pre- and post-synapse to be functionally correlated and that subsets of synapses are more susceptible to certain forms of synaptic plasticity. As presynaptic function is often examined in isolation from postsynaptic properties, the effect it has on the post-synapse is not fully understood. However, since postsynaptic receptors at excitatory synapses respond to release of glutamate, it follows that they may be differentially regulated depending on the frequency of its release. Therefore, examining postsynaptic properties in the context of presynaptic function may be a useful way to approach a broad range of questions on synaptic physiology. In this review, we focus on how optophysiology tools have been utilized to study relationships between the pre- and the post-synapse. Multiple imaging techniques have revealed correlations in synaptic properties from the submicron to the dendritic level. Optical tools together with advanced imaging techniques are ideally suited to illuminate this area further, due to the spatial resolution and control they allow.
Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Humans; Neuronal Plasticity; Presynaptic Terminals; Receptors, AMPA; Synapses; Synaptic Potentials; Synaptic Transmission
PubMed: 32308573
DOI: 10.3389/fncir.2020.00009 -
The Journal of Physiology Jan 2022Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at... (Review)
Review
Decades of literature indicate that the AMPA-type glutamate receptor is among the fastest acting of all neurotransmitter receptors. These receptors are located at excitatory synapses, and conventional wisdom says that they activate in hundreds of microseconds, deactivate in milliseconds due to their low affinity for glutamate and also desensitize profoundly. These properties circumscribe AMPA receptor activation in both space and time. However, accumulating evidence shows that AMPA receptors can also activate with slow, indefatigable responses. They do so through interactions with auxiliary subunits that are able promote a switch to a high open probability, high-conductance 'superactive' mode. In this review, we show that any assumption that this phenomenon is limited to heterologous expression is false and rather that slow AMPA currents have been widely and repeatedly observed throughout the nervous system. Hallmarks of the superactive mode are a lack of desensitization, resistance to competitive antagonists and a current decay that outlives free glutamate by hundreds of milliseconds. Because the switch to the superactive mode is triggered by activation, AMPA receptors can generate accumulating 'pedestal' currents in response to repetitive stimulation, constituting a postsynaptic mechanism for short-term potentiation in the range 5-100 Hz. Further, slow AMPA currents span 'cognitive' time intervals in the 100 ms range (theta rhythms), of particular interest for hippocampal function, where slow AMPA currents are widely expressed in a synapse-specific manner. Here, we outline the implications that slow AMPA receptors have for excitatory synaptic transmission and computation in the nervous system.
Topics: Glutamic Acid; Patch-Clamp Techniques; Receptors, AMPA; Synapses; Synaptic Transmission
PubMed: 34587649
DOI: 10.1113/JP280877 -
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 -
Journal of Translational Medicine Aug 2023The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent...
Inhibiting NLRP3 inflammasome signaling pathway promotes neurological recovery following hypoxic-ischemic brain damage by increasing p97-mediated surface GluA1-containing AMPA receptors.
BACKGROUND
The nucleotide-binding oligomeric domain (NOD)-like receptor protein 3 (NLRP3) inflammasome is believed to be a key mediator of neuroinflammation and subsequent secondary brain injury induced by ischemic stroke. However, the role and underlying mechanism of the NLRP3 inflammasome in neonates with hypoxic-ischemic encephalopathy (HIE) are still unclear.
METHODS
The protein expressions of the NLRP3 inflammasome including NLRP3, cysteinyl aspartate specific proteinase-1 (caspase-1) and interleukin-1β (IL-1β), the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionicacid receptor (AMPAR) subunit, and the ATPase valosin-containing protein (VCP/p97), were determined by Western blotting. The interaction between p97 and AMPA glutamate receptor 1 (GluA1) was determined by co-immunoprecipitation. The histopathological level of hypoxic-ischemic brain damage (HIBD) was determined by triphenyltetrazolium chloride (TTC) staining. Polymerase chain reaction (PCR) and Western blotting were used to confirm the genotype of the knockout mice. Motor functions, including myodynamia and coordination, were evaluated by using grasping and rotarod tests. Hippocampus-dependent spatial cognitive function was measured by using the Morris-water maze (MWM).
RESULTS
We reported that the NLRP3 inflammasome signaling pathway, such as NLRP3, caspase-1 and IL-1β, was activated in rats with HIBD and oxygen-glucose deprivation (OGD)-treated cultured primary neurons. Further studies showed that the protein level of the AMPAR GluA1 subunit on the hippocampal postsynaptic membrane was significantly decreased in rats with HIBD, and it could be restored to control levels after treatment with the specific caspase-1 inhibitor AC-YVAD-CMK. Similarly, in vitro studies showed that OGD reduced GluA1 protein levels on the plasma membrane in cultured primary neurons, whereas AC-YVAD-CMK treatment restored this reduction. Importantly, we showed that OGD treatment obviously enhanced the interaction between p97 and GluA1, while AC-YVAD-CMK treatment promoted the dissociation of p97 from the GluA1 complex and consequently facilitated the localization of GluA1 on the plasma membrane of cultured primary neurons. Finally, we reported that the deficits in motor function, learning and memory in animals with HIBD, were ameliorated by pharmacological intervention or genetic ablation of caspase-1.
CONCLUSION
Inhibiting the NLRP3 inflammasome signaling pathway promotes neurological recovery in animals with HIBD by increasing p97-mediated surface GluA1 expression, thereby providing new insight into HIE therapy.
Topics: Mice; Animals; Rats; Inflammasomes; NLR Family, Pyrin Domain-Containing 3 Protein; Receptors, AMPA; Hypoxia-Ischemia, Brain; Signal Transduction; Caspase 1; Brain
PubMed: 37620837
DOI: 10.1186/s12967-023-04452-5 -
International Journal of Molecular... Jan 2023Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents.... (Review)
Review
Since the 1990s, ionotropic glutamate receptors have served as an outstanding target for drug discovery research aimed at the discovery of new neurotherapeutic agents. With the recent approval of perampanel, the first marketed non-competitive antagonist of AMPA receptors, particular interest has been directed toward 'non-NMDA' (AMPA and kainate) receptor inhibitors. Although the role of AMPA receptors in the development of neurological or psychiatric disorders has been well recognized and characterized, progress in understanding the function of kainate receptors (KARs) has been hampered, mainly due to the lack of specific and selective pharmacological tools. The latest findings in the biology of KA receptors indicate that they are involved in neurophysiological activity and play an important role in both health and disease, including conditions such as anxiety, schizophrenia, epilepsy, neuropathic pain, and migraine. Therefore, we reviewed recent advances in the field of competitive and non-competitive kainate receptor antagonists and their potential therapeutic applications. Due to the high level of structural divergence among the compounds described here, we decided to divide them into seven groups according to their overall structure, presenting a total of 72 active compounds.
Topics: Humans; Receptors, Kainic Acid; Receptors, AMPA; Epilepsy; Mental Disorders
PubMed: 36768227
DOI: 10.3390/ijms24031908 -
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