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Glutamate receptor ion channels
Mark L Mayer
Glutamate receptor ion channels mediate excitatory responses at the majority of CNS synapses. They are the only ligand-gated ion channels for which multiple high-resolution crystal structures have been solved. Highlights of information gained from mechanistic studies based on the crystal structures of their ligand-binding domains include explanationsfor strikingly diverse phenomena. These include the basis for subtype-specific agonist selectivity; mechanisms for desensitization and allosteric modulation; and mechanisms for partial agonist activity. In addition, multiple lines of evidence, including low-resolution electron microscopic studies, suggest that native AMPA receptors combine with an auxiliary subunit which regulates activity andtrafficking. Functional studies suggest that glutamate receptor gating is distinct from that of structurally related voltage-gated ion channels.
Addresses Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, Building 35 Room 3B 1002 MSC 3712, 35 Lincoln Drive, Bethesda MD, 20892 3712, USA Corresponding author: Mayer, Mark L (mayerm@mail.nih.gov)

CurrentOpinion in Neurobiology 2005, 15:282–288 This review comes from a themed issue on Signalling mechanisms Edited by Lily Y Jan and Steven A Siegelbaum Available online 24th May 2005 0959-4388/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.conb.2005.05.004

Introduction
Ligand-gated ion channels are membrane proteins that mediate information transfer at synapses. Their function relies onthe ability to respond very rapidly to the transient release of a neurotransmitter to produce a change in membrane potential of the postsynaptic cell. Genome and cDNA sequencing analysis reveals that there are three major subtypes of neurotransmitter activated ligand-gated ion channel, each with a unique architecture. These are the glutamate receptors, tetrameric cationselective channels that areactivated by glutamate and several environmentally significant plant neurotoxins; the so-called cys-loop receptors, which form pentameric ion channels gated by acetylcholine, g-aminobutyric acid, glycine and serotonin; and the P2X receptors which are believed to be trimeric ion channels gated by ATP.
Current Opinion in Neurobiology 2005, 15:282–288

The glutamate receptor ion channels (iGluRs)are abundantly expressed in the brain and spinal cord and mediate responses at the vast majority of excitatory synapses. Mammalian iGluRs are encoded by 18 genes that assemble to form four major families, the AMPA, kainate, NMDA and delta receptors. There are four AMPA receptor genes (GluR1–4); five kainate receptor genes (GluR5– 7, plus KA1 and KA2); seven NMDA receptor genes (NR1, NR2A-D, NR3A andNR3B); and two delta subunits. Coassembly of iGluRs within, but not between, families generates a large number of receptor subtypes in vivo. Unique among ligand-gated ion channels, highresolution crystal structures have been obtained for multiple subtypes of iGluRs, and such structures provide the means to gain unprecedented insight into their mechanism of action and modulation. The uniquearchitecture of iGluRs is a key factor that has facilitated their structural analysis (Figure 1). Unlike the cys-loop receptors, in which ligand-binding sites are formed at the interface between subunits, in iGluRs the ligand-binding cores are discrete domains, one copy of which is present in each subunit. The ligand-binding domains can be genetically excised, expressed as water-soluble proteins andcrystallized. To date, structural analysis has been successfully applied to the ligand-binding cores of a-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) [1], kainate [2] and N-methyl-D-aspartic acid (NMDA) [3] receptors; work is ongoing in several laboratories on other iGluR domains but the experience gained indicates that these are more challenging targets. As a result of this...