Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins

Yael Stern-Bach*, Bernhard Bettler, Melissa Hartley, Paul O. Sheppard, Patrick J. O'Hara, Stephen F. Heinemann

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

398 Scopus citations

Abstract

By exchanging portions of the AMPA receptor subunit GluR3 and the kainate receptor subunit GluR6, we have identified two discontinuous segments of approximately 150 amino acid residues each that control the agonist pharmacology of these glutamate receptors. The first segment (S1) is adjacent and N-terminal to the putative transmembrane domain 1 (TM1), whereas the second segment (S2) is located between the putative TM3 and TM4. Only the simultaneous exchange of S1 and S2 converts the pharmacological profile of the recipient to that of the donor subunit. The two segments identified in this study share sequence similarities with the ligand-binding site of several bacterial periplasmic amino acid-binding proteins. Based on the X-ray structure of these proteins, we propose a model for the glutamate-binding site of ionotropic glutamate receptors.

Original languageAmerican English
Pages (from-to)1345-1357
Number of pages13
JournalNeuron
Volume13
Issue number6
DOIs
StatePublished - Dec 1994
Externally publishedYes

Bibliographical note

Funding Information:
We thank Richard Huganir (Johns Hopkins University, Baltimore, MD) for the gift of antibodies, Jacques Barhanin (Institute for Molecular and Cellular Pharmacology, Valbonne, France) for providing the cigale software, Lilly Research Laboratories (Indianapolis, IN) for the gift of cyclothiazide, Emily Liman (Harvard Medical School, Boston, MA) for the pGEMHE vector, Domenick Venezia for computer algorithms, B. H. Oh and S. H. Kim for kindly providing the LAOBP coordinates before release in the Protein Database, and W. Pearson and M. Gribskov for software. We also thank Jim Boulter, Cheryl Rogers, Douglas Vetter, and Robert Petroski for critically reading the manuscript, Chris Boyer for preparing the Xenopus oocytes, and Jamie Simon from the Saik Institute photography and graphics department for help with the figures.This work was supported by the Human Frontier Science Program Organization (H FSPO) fellowship and research grant LT-315/92 (Y. S. B.), a Swiss National Science Foundation fellowship for Advanced Researchers $23A-030712 (B. B.), National Institute of Neurological and Communicative Disorders and Stroke grant NS28709 (S. F. H.), and the McKnight Foundation (S. F. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 USC Section 1734 solely to indicate this fact.

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