Structural aspects of AMPA receptor activation, desensitization and deactivation

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Glutamate mediates most of the excitatory neurotransmission in the mammalian central nervous system by activating ionotropic glutamate receptors. Structural and functional studies of ionotropic glutamate receptors have offered detailed insight into the mechanism by which these integral membrane proteins function. In particular, advances in our understanding of the atomic structure of the agonist-binding domain have provided new opportunities to consider the conformational changes that take place in a functioning ligand-gated ion channel. Several recent studies have turned up important new ideas about the structural determinants of channel activation, deactivation and desensitization of AMPA receptors. Working hypotheses derived from this structural insight offer a rare opportunity to enrich and guide functional studies.

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).

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