Structural aspects of AMPA receptor activation, desensitization and deactivation
Introduction
When glutamate is released from the presynaptic membrane during fast excitatory neurotransmission, it readily diffuses across the synaptic cleft and activates ionotropic glutamate receptors (iGluRs) present the postsynaptic membrane. The resulting excitatory postsynaptic current is typically mediated by members of two different functional classes of iGluRs: NMDA receptors and AMPA receptors [1, 2]. Although NMDA receptors and AMPA receptors are closely related, their functional properties are highly specialized and their characteristic functional signatures are pivotal in downstream events that are important for processes such as neural development and synaptic plasticity [3, 4, 5]. AMPA receptor channels display fast kinetics, meaning that activation, deactivation and desensitization occur within milliseconds, whereas NMDA receptor channels display slower kinetics [1, 2]. Although kainate receptors, the third functional class of iGluR, also take part in glutamate-mediated neurotransmission, they exhibit strong desensitization and slow recovery from desensitization, which could complicate their frequency response [2, 6].
Structural understanding of iGluR function has long been sought. In particular, there has been remarkable progress in the past decade towards understanding the structural basis for many of the functional properties of AMPA receptors, such as agonist binding, partial agonism, desensitization and allosteric modulation. Here, we review recent advances in our structural understanding of AMPA receptors that have suggested important new ideas about the conformational changes that are induced upon agonist binding and lead to channel activation and desensitization.
Section snippets
Ligand-induced conformations of the ABD and channel activation
Efforts to prepare X-ray crystal structures of full-length iGluR subunits have so far been unsuccessful, but high-resolution X-ray crystal structures of the isolated agonist-binding domains (ABDs) from several different iGluR subunits are now available (Figure 1). Numerous crystal structures of the isolated ABD of the AMPA receptor subunit GluR2 have been obtained either without bound ligand (apo-form) or in complex with a wide range of different ligands. These structures demonstrate that the
Interdomain contacts in the agonist-bound ABD
In a recent study, Robert et al. asked a simple question [26••]: how does the stability of the closed conformation of the agonist-bound ABD influence receptor properties? Using mutagenesis with the ABD crystal structures as guide, Robert et al. [26••] disrupted an interdomain contact that was absent in the open conformation of the ABD but was hypothesized to stabilize the closed conformation of the agonist-bound ABD. Specifically, they removed an interdomain contact between a glutamate residue
Rearrangements at the subunit interface and channel desensitization
It is now evident in full-length iGluRs that the stability of the interactions at the dimer interface is greatly reduced upon agonist binding, and that this instability leads to a rearrangement of the dimer interface [9, 10, 11•, 12, 35••, 36•]. Agonist-induced domain closure in the ABD implies that D1 and D2 move relative to each other, resulting in instability at the TMD and at the dimer interface. Stability can be restored either by domain reopening or by rearrangement at the dimer
Auxiliary AMPA receptor subunits
Recent studies have provided low-resolution electron microscopy images of purified recombinant and native AMPA receptors [43, 44•, 45]. Furthermore, application of antibodies to localize the ABD and the N-terminal domain (NTD) have enabled surface contour to be evaluated, and thus the ABD and NTD to be localized in the absence and presence of glutamate [44•]. From the images, it is clear that continuous presence of glutamate leads to a substantial rearrangement of the NTD relative to the ABD.
Conclusions
Although we still have little information on structure and dynamic behavior of full-length iGluRs, the X-ray crystal structures of the isolated ABDs have provided testable hypotheses that, through clever experimentation, have shaped our conceptual models for the relationships between AMPA receptor activation, desensitization and deactivation. Domains other than the ABD are still unexplored; a major challenge will be to resolve the interaction between these domains and their influence on
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Dr Mark Mayer for helpful comments on the manuscript. This work was supported by the National Institutes of Health (SFT), NARSAD (SFT), the Michael J Fox Foundation (SFT) and the Alfred Benzon Foundation (KBH).
References (56)
- et al.
Homeostatic plasticity and NMDA receptor trafficking
Trends Neurosci
(2005) - et al.
Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core
Neuron
(2000) - et al.
Structural basis for AMPA receptor activation and ligand selectivity: crystal structures of five agonist complexes with the GluR2 ligand-binding core
J Mol Biol
(2002) - et al.
Regulation of AMPA receptor gating by ligand binding core dimers
Neuron
(2004) - et al.
Stereochemistry of glutamate receptor agonist efficacy: engineering a dual-specificity AMPA/kainate receptor
Biochemistry
(2004) - et al.
Evolution of glutamate interactions during binding to a glutamate receptor
Nat Chem Biol
(2005) - et al.
Competitive antagonism of AMPA receptors by ligands of different classes: crystal structure of ATPO bound to the GluR2 ligand-binding core, in comparison with DNQX
J Med Chem
(2003) - et al.
Tyr702 is an important determinant of agonist binding and domain closure of the ligand-binding core of GluR2
Mol Pharmacol
(2005) - et al.
Functional stoichiometry of glutamate receptor desensitization
J Neurosci
(2002) - et al.
Targeting of AMPA receptor gating processes by allosteric modulators and mutations
Biophys J
(2007)
The Three-dimensional structure of an ionotropic glutamate receptor reveals a dimer-of-dimers assembly
J Mol Biol
Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor channels lacking the N-terminal domain
J Biol Chem
Two regions in the N-terminal domain of ionotropic glutamate receptor 3 form the subunit oligomerization interfaces that control subtype-specific receptor assembly
J Biol Chem
Subtype-specific assembly of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor subunits is mediated by their n-terminal domains
J Biol Chem
Stargazin reduces desensitization and slows deactivation of the AMPA-type glutamate receptors
J Neurosci
Stargazin modulates AMPA receptor gating and trafficking by distinct domains
Nature
Stargazin modulates native AMPA receptor functional properties by two distinct mechanisms
J Neurosci
A novel action of stargazin as an enhancer of AMPA receptor activity
Neurosci Res
The glutamate receptor ion channels
Pharmacol Rev
Glutamate receptor gating
Crit Rev Neurobiol
A unified model of the presynaptic and postsynaptic changes during LTP at CA1 synapses
Sci STKE
AMPA receptor trafficking and synaptic plasticity
Annu Rev Neurosci
Roles and rules of kainate receptors in synaptic transmission
Nat Rev Neurosci
Structural basis for partial agonist action at ionotropic glutamate receptors
Nat Neurosci
Mechanism of positive allosteric modulators acting on AMPA receptors
J Neurosci
Mechanism of glutamate receptor desensitization
Nature
Agonist-induced isomerization in a glutamate receptor ligand-binding domain. A kinetic and mutagenetic analysis
J Biol Chem
Structural mobility of the extracellular ligand-binding core of an ionotropic glutamate receptor. Analysis of NMR relaxation dynamics
Biochemistry
Cited by (56)
AMPA receptor neurotransmission and therapeutic applications: A comprehensive review of their multifaceted modulation
2024, European Journal of Medicinal ChemistryUrocanic acid facilitates acquisition of object recognition memory in mice
2023, Physiology and BehaviorDruggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain
2019, StructureCitation Excerpt :Extensive functional and structural data show that channel gating is coupled to closure of the LBD clamshell upon agonist binding (Greger et al., 2017). In AMPARs, prolonged agonist binding also triggers desensitization where rearrangement within LBD dimers relieves the tension on the TMD to allow channel closure with agonist remaining bound (Armstrong et al., 2006; Hansen et al., 2007; Horning and Mayer, 2004; Sun et al., 2002). A number of positive allosteric modulators target the interface between LBD dimers (Figure 1A, inset; designated as D1), which results in dimer stabilization and attenuated desensitization (Jin et al., 2005; Partin, 2015; Sun et al., 2002).
Synaptic Organization of the Cerebral Cortex
2015, Brain Mapping: An Encyclopedic ReferenceStructure-function correlates of glutamate-gated ion channels
2012, Comprehensive Biophysics