Sci. Signal., 15 December 2009
Glutamate Receptors Exciting Structures
John F. Foley
Science Signaling, AAAS, Washington, DC 20005, USA
Glutamate is an excitatory neurotransmitter, which when released into the synapse activates metabotropic and ionotropic glutamate receptors in postsynaptic cells. Ionotropic glutamate receptors (iGluRs), such as AMPA, NMDA, and kainate receptors, are ligand-gated ion channels consisting of tetramers of receptor subunits containing amino-terminal domains (ATDs), ligand-binding domains (LBDs), and transmembrane domains (TMDS), which form the ion channel (see Wollmuth and Traynelis). Whereas previous studies have focused on individual domains of various iGluRs, Sobolevsky et al. solved the x-ray crystal structure of the full-length rat AMPA receptor, a homotetramer of GluA2 subunits, bound to an antagonist. The structure resembled a "Y," with the ATDs at the prongs, the TMDs at the base, and the LBDs between the two. Whereas the extracellular ATDs and LBDs consisted of pairs of dimers arranged around two-fold axes of symmetry, the TMDs exhibited a four-fold, rotational axis of symmetry. Substantial crossover of the subunits (A to D) resulted in domain-swapping in the extracellular regions. Thus, the dimer pairs at the level of the ATDs were A-B and C-D, whereas at the lower level of the LBDs, the pairs were A-D and B-C. The authors found similar structural features in NMDA receptors made up of GluN1 and GluN2 subunits. Analysis of the structure of the TMDs and the ion channel of the AMPA receptor, which was closed because of the antagonist, revealed similarities with the pores of K+ channels. Based on the structure as a whole, the authors proposed mechanisms for the action, desensitization, and inhibition of the AMPA receptor, which they suggest can be applied to iGluRs in general.
A. I. Sobolevsky, M. P. Rosconi, E. Gouaux, X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature 462, 745–756 (2009). [PubMed]
L. P. Wollmuth, S. F. Traynelis, Excitatory view of a receptor. Nature 462, 729–731 (2009). [Online Journal]
Citation: J. F. Foley, Exciting Structures. Sci. Signal. 2, ec398 (2009).
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