A point mutation in the glutamate binding site blocks desensitization of AMPA receptors

Yael Stern-Bach, Sebastian Russo, Menahem Neuman, Christian Rosenmund

Research output: Contribution to journalArticlepeer-review

217 Scopus citations

Abstract

Desensitization of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors is thought to shape the synaptic response and act as a neuroprotective mechanism at central synapses, but the molecular mechanism underlying desensitization is poorly understood. We found that replacing the glutamate binding domain S1 of GluR3 (an AMPA receptor) with S1 of GluR6 (a kainate receptor) resulted in a fully active but completely nondesensitizing receptor. Smaller substitutions within S1 identified, besides two additional modulatory regions, a single exchange, L507Y, as is required and sufficient for the block of desensitization. This phenotype was specific for AMPA receptors and required an aromatic residue at this position. L507 lies between two residues (T504 and R509) that form part of the glutamate binding site. The physical proximity of these residues, which are involved in binding and gating, suggests they may form part of the link between these two events.

Original languageAmerican English
Pages (from-to)907-918
Number of pages12
JournalNeuron
Volume21
Issue number4
DOIs
StatePublished - Oct 1998

Bibliographical note

Funding Information:
We are grateful to S. Heinemann for supporting the initial stages of the research and thank M. Hartley for sequencing part of the mutants. We thank A. Boxall, T. Green, S. Heinemann, E. Huang, J. Lerma, J. Mosbacher, C. F. Stevens, and G. Swanson for discussion and critical reading of the manuscript. We thank S. Schmidt and I. Herfort for maintaining the cell culture, O. Livnah for help with Figure 7B . Seed for the provision of the CD8 vector, and Eli Lilly for the gift of cyclothiazide. This research was supported by a United States-Israel binational Science Foundation grant (Y. S.-B.) and by the Max-Planck Society and a Helmholtz fellowship (C. R.).

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