Trends in Biochemical Sciences
ReviewEmerging structural insights into the function of ionotropic glutamate receptors
Section snippets
A brief history of structural studies on iGluRs
Glutamate, a simple amino acid, is the major excitatory neurotransmitter in mammalian brains [1]. The presynaptically released glutamate binds different subclasses of ionotropic glutamate receptors (iGluRs) including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs), kainate receptors, and N-methyl-D-aspartate (NMDA) receptors (NMDARs). Glutamate binding mediates opening of their cationic ion channels to generate synaptic current pivotal to brain function. The iGluR
Structural biology of intact non-NMDARs – a giant step toward mechanistic understanding
Recently several intact non-NMDAR structures have been published by multiple groups, providing solid molecular templates that permit a mechanistic understanding of their activation and desensitization. Specifically, in addition to the original GluA2 AMPAR structure in the antagonist-bound form, GluA2 AMPAR structures in the pre-activated (or pre-open) state, and structures of the desensitized state of GluA2 AMPAR and GluK2 kainate receptor (obtained by both X-ray crystallography and cryo-EM),
The first visualization of NMDAR heterotetramers
Because several structural studies of NMDAR ATDs revealed a large difference in their architecture as well as pattern of subunit interactions from non-NMDAR ATDs, it became clear that the mode of ATD and LBD interaction and subunit assembly in NMDARs would be distinct from that in non-NMDARs, and thus the AMPAR model cannot be extrapolated to study NMDARs 25, 26, 27, 28. In the wake of substantial enthusiasm to obtain the structure of the intact NMDAR, two very similar structures were published
Concluding remarks
The structural studies of iGluRs are now entering a new, exciting phase in which the intact tetrameric structures of all of the major iGluR subclasses are revealed. Structural studies of iGluRs are not only important for the understanding of general mechanisms underlying functional regulation (ligand-gating, channel opening, allosteric regulation, etc.) but also to visualize pharmacological binding sites useful for the development of therapeutic compounds (Figure 6). While significant insights
Acknowledgments
We thank Eric Gouaux for providing the structural coordinates for the desensitized AMPAR. Mark Mayer, Sasha Sobolevsky, Andrew Plested, Katharina Dürr, Lei Chen, Chia-Hsueh Lee, and Xianqiang Song are thanked for open discussion on the topics in this review at the 59th Biophysical Society meeting. This work was supported by the National Institutes of Health (MH085926 and GM105730 to H.F.), the Stanley Institute of Cognitive Genomics, and the Robertson Research Fund of Cold Spring Harbor
References (78)
- et al.
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core
Neuron
(2000) Structural insights into competitive antagonism in NMDA Receptors
Neuron
(2014)Crystal structures of the GluR5 and GluR6 ligand binding cores: molecular mechanisms underlying kainate receptor selectivity
Neuron
(2005)Crystal structure of the GluR2 amino-terminal domain provides insights into the architecture and assembly of ionotropic glutamate receptors
J. Mol. Biol.
(2009)- et al.
Crystal structures of the glutamate receptor ion channel GluK3 and GluK5 amino-terminal domains
J. Mol. Biol.
(2010) Structure and assembly mechanism for heteromeric kainate receptors
Neuron
(2011)The three-dimensional structure of an ionotropic glutamate receptor reveals a dimer-of-dimers assembly
J. Mol. Biol.
(2004)A novel Conus snail polypeptide causes excitotoxicity by blocking desensitization of AMPA receptors
Curr. Biol.
(2009)Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states
Cell
(2014)- et al.
Automatic cryo-EM particle selection for membrane proteins in spherical liposomes
J. Struct. Biol.
(2014)