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Mechanism of glutamate receptor desensitization

Nature volume 417, pages 245–253 (2002)Cite this article

Abstract

Ligand-gated ion channels transduce chemical signals into electrical impulses by opening a transmembrane pore in response to binding one or more neurotransmitter molecules. After activation, many ligand-gated ion channels enter a desensitized state in which the neurotransmitter remains bound but the ion channel is closed. Although receptor desensitization is crucial to the functioning of many ligand-gated ion channels in vivo, the molecular basis of this important process has until now defied analysis. Using the GluR2 AMPA-sensitive glutamate receptor, we show here that the ligand-binding cores form dimers and that stabilization of the intradimer interface by either mutations or allosteric modulators reduces desensitization. Perturbations that destabilize the interface enhance desensitization. Receptor activation involves conformational changes within each subunit that result in an increase in the separation of portions of the receptor that are linked to the ion channel. Our analysis defines the dimer interface in the resting and activated state, indicates how ligand binding is coupled to gating, and suggests modes of dimer–dimer interaction in the assembled tetramer. Desensitization occurs through rearrangement of the dimer interface, which disengages the agonist-induced conformational change in the ligand-binding core from the ion channel gate.

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Figure 1: The L483Y mutation and CTZ promote dimerization and block desensitization.
Figure 2: The L483Y mutation and CTZ stabilize the GluR2 S1S2J dimer.
Figure 3: Disruption of the Tyr 483 binding site at the dimer interface increases the extent of receptor desensitization and shifts the S1S2J monomer–dimer equilibrium towards monomer.
Figure 4: Introduction of aspartate at position 754 accelerates desensitization and reveals a new, ‘lateral’ mode by which the ligand-binding cores can interact.
Figure 5: Agonist-induced conformational changes in the dimer and gating model.

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Acknowledgements

We thank L. Lu and C. Glasser for technical assistance, J. Lidestri for maintenance of the X-ray laboratory at Columbia University, and W. N. Zagotta and S. Harrison for helpful discussions. Synchrotron diffraction data were collected at the x4a beamline at the National Synchrotron Light Source. The XL-I ultracentrifuge was obtained with funds provided by the NIH. This work was supported by the Klingenstein Foundation (E.G.), the National Alliance for Research on Schizophrenia and Depression (E.G) and the NIH (E.G., M.L.M.). E.G. is also an assistant investigator of the Howard Hughes Medical Institute.

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Author notes

  1. Yu Sun, Rich Olson, Michelle Horning and Eric Gouaux: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168th Street, New York, New York, 10032, USA

    Yu Sun, Rich Olson, Neali Armstrong & Eric Gouaux

  2. Howard Hughes Medical Institute, Columbia University, 650 West 168th Street, New York, New York, 10032, USA

    Eric Gouaux

  3. Laboratory of Cellular and Molecular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, 20892, USA

    Michelle Horning & Mark Mayer

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Sun, Y., Olson, R., Horning, M. et al. Mechanism of glutamate receptor desensitization. Nature 417, 245–253 (2002). https://doi.org/10.1038/417245a

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