AMPA receptors (AMPARs) are tetrameric ion channels that, together with other ionotropic glutamate receptors (iGluRs), the NMDA, and kainate receptors, mediate a majority of excitatory neurotransmission in the central nervous system. (Greger et al., 2017)
Glutamate is by far the most abundant neurotransmitter used by excitatory synapses in the vertebrate central nervous system. Once released into the synaptic cleft, it depolarises the postsynaptic membrane and activates downstream signaling pathways, resulting in the propagation of the excitatory signal. Initial depolarisation is primarily mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors. These ion channels are the first ones to be activated by released glutamate, and their kinetics, dynamics, and abundance on the postsynaptic membrane define the strength of the postsynaptic response. (Baranovic, 2021)
The fact that AMPA receptors play a dominant role throughout the brain raises the significant challenge of selectively targeting only those regions affected by disease, and clinical trials have raised doubt regarding the feasibility of specifically targeting AMPA receptors for new therapeutic options. (Lee et al, 2016)
Greger IH, Watson JF, Cull-Candy SG. Structural and Functional Architecture of AMPA-Type Glutamate Receptors and Their Auxiliary Proteins. Neuron. 2017 May 17;94(4):713-730. doi: 10.1016/j.neuron.2017.04.009. PMID: 28521126.
Baranovic J. AMPA receptors in the synapse: Very little space and even less time. Neuropharmacology. 2021 Sep 15;196:108711. doi: 10.1016/j.neuropharm.2021.108711. Epub 2021 Jul 13. PMID: 34271021.
Lee K, Goodman L, Fourie C, Schenk S, Leitch B, Montgomery JM. AMPA Receptors as Therapeutic Targets for Neurological Disorders. Adv Protein Chem Struct Biol. 2016;103:203-61. doi: 10.1016/bs.apcsb.2015.10.004. Epub 2015 Nov 19. PMID: 26920691.
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