Abstract
AMPA-type glutamate receptors are specifically inhibited by the noncompetitive antagonists GYKI-53655 and CP-465,022, which act through sites and mechanisms that are not understood. Using receptor mutagenesis, we found that these antagonists bind at the interface between the S1 and S2 glutamate binding core and channel transmembrane domains, specifically interacting with S1-M1 and S2-M4 linkers, thereby disrupting the transduction of agonist binding into channel opening. We also found that the antagonists' affinity is higher for agonist-unbound receptors than for activated nondesensitized receptors, further depending on the level of S1 and S2 domain closure. These results provide evidence for substantial conformational changes in the S1-M1 and S2-M4 linkers following agonist binding and channel opening, offering a conceptual frame to account for noncompetitive antagonism of AMPA receptors.
| Original language | English |
|---|---|
| Pages (from-to) | 279-288 |
| Number of pages | 10 |
| Journal | Neuron |
| Volume | 48 |
| Issue number | 2 |
| DOIs | |
| State | Published - 20 Oct 2005 |
Bibliographical note
Funding Information:This work was supported by grants from the Israel Science Foundation (Y.S.-B.), the Israeli Ministry of Health (Y.S.-B.), the Spanish Ministry of Education and Science (J.L.), and by an Israeli-Spanish Scientific Cooperation grant from the Israeli Ministry of Science and the Spanish Ministry of Foreign Affairs (Y.S.-B. and J.L.). V.B. is a recipient of a scholarship from the Bernard Katz Minerva Center for Cell Biophysics. We thank Eli Lilly and Company for the gift of GYKI-53655 (LY300168) and E. Gouaux and N. Armstrong for R2(L650T). We thank M. Dahan-Fumber, who participated in the preliminary stages of the work, and N. Parikh for work on the [ 3 H]CP-526,427 binding assays. We also thank M. Treinin and Z. Siegfried for discussion.