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. 2011 Mar;11(2):56-63.
doi: 10.5698/1535-7511-11.2.56.

Revisiting AMPA receptors as an antiepileptic drug target

Michael A Rogawski  1
Affiliations

Revisiting AMPA receptors as an antiepileptic drug target

Michael A Rogawski. Epilepsy Curr. 2011 Mar.

Abstract

In the 1990s there was intense interest in ionotropic glutamate receptors as therapeutic targets for diverse neurological disorders, including epilepsy. NMDA receptors were thought to play a key role in the generation of seizures, leading to clinical studies of NMDA receptor blocking drugs in epilepsy. Disappointing results dampened enthusiasm for ionotropic glutamate receptors as a therapeutic target. Eventually it became appreciated that another type of ionotropic glutamate receptor, the AMPA receptor, is actually the predominant mediator of excitatory neurotransmission in the central nervous system and moreover that AMPA receptors are critical to the generation and spread of epileptic activity. As drugs became available that selectively target AMPA receptors, it was possible to demonstrate that AMPA receptor antagonists have powerful antiseizure activity in in vitro and in vivo models. A decade later, promising clinical studies with AMPA receptor antagonists, including the potent noncompetitive antagonist perampanel, are once again focusing attention on AMPA receptors as a drug target for epilepsy therapy.

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Figures

Fig. 1.
Fig. 1.
Schematic excitatory synapse. When action potentials mediated by voltage-gated sodium and potassium channels invade the presynaptic terminal, voltage-gated calcium channels are activated. Calcium entering through the channels stimulates glutamate release from synaptic vesicles, which diffuses across the synaptic cleft to activate AMPA receptors, generating the EPSP, a fast membrane depolarization. With strong stimulation, NMDA receptors are activated eliciting various forms of synaptic plasticity. In a simplified view of long-term potentiation, the calcium entering through NMDA receptors binds to calmodulin, which activates calcium- and calmodulin-dependent protein kinase II (CaMKII) that trafficks AMPA receptors into the extrasynaptic plasma membrane from where they become concentrated by lateral diffusion to synaptic sites. The oval abutting the AMPA receptor represents the various auxiliary subunits, including TARPs, cornichon proteins, SynDIG1 and others, that are associated with AMPA receptors and regulate their function and trafficking.
Fig. 2.
Fig. 2.
Current model of the protein architecture of the AMPA receptor. Left, view of the broad face of a tetrameric AMPA receptor as determined by X-ray crystallography. Each subunit is in a different color. Adapted from ref. 6 by permission of Macmillan Publishers Ltd., copyright 2009. Right, domain structure of a single AMPA receptor subunit consisting of a bilobed amino-terminal domain, a two-domain ligand-binding core (D1–D2) that serves as the binding site for competitive antagonists, linker segments to which noncompetitive antagonists bind (S1–M1, S2–M4), an ion channel with three membrane-spanning segments (M1–M3, where M3 lines the pore) and a pore loop (M2), and a carboxy-terminal cytoplasmic domain. Agonists, including the natural agonist glutamate, bind to D1 and then the flexible D2 moves towards D1. This movement is thought to pull apart the linkers to the transmembrane channel thus changing the orientation of the transmembrane domains leading to the opening of the ion channel. Binding of noncompetitive antagonists stabilize a configuration of the linkers so that agonist binding fails to induce gating of the channel.
Fig. 3.
Fig. 3.
Structures of noncompetitive AMPA receptor antagonists.
See this image and copyright information in PMC

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References

    1. Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM, Ogden KK, Hansen KB, Yuan H, Myers SJ, Dingledine R. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev. 2010;62:405–496. - PMC - PubMed
    1. Megías M, Emri Z, Freund TF, Gulyás AI. Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells. Neuroscience. 2001;102:527–540. - PubMed
    1. Laezza F, Dingledine R. Induction and expression rules of synaptic plasticity in hippocampal interneurons. Neuropharmacology. 2010;60:720–729. - PMC - PubMed
    1. Hollmann M, O'Shea-Greenfield A, Rogers SW, Heinemann S. Cloning by functional expression of a member of the glutamate receptor family. Nature. 1989;342(6250):643–648. - PubMed
    1. Lodge D. The history of the pharmacology and cloning of ionotropic glutamate receptors and the development of idiosyncratic nomenclature. Neuropharmacology. 2009;56:6–21. - PubMed