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J. Biol. Chem., Vol. 280, Issue 33, 29708-29716, August 19, 2005

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Conserved Structural and Functional Control of N-Methyl-D-aspartate Receptor Gating by Transmembrane Domain M3^*

Hongjie Yuan, Kevin Erreger, Shashank M. Dravid, and Stephen F. Traynelis

From the Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322-3090

The molecular events controlling glutamate receptor ion channel gating are complex. The movement of transmembrane domain M3 within N-methyl-D-aspartate (NMDA) receptor subunits has been suggested to be one structural determinant linking agonist binding to channel gating. Here we report that covalent modification of NR1-A652C or the analogous mutation in NR2A, -2B, -2C, or -2D by methanethiosulfonate ethylammonium (MT-SEA) occurs only in the presence of glutamate and glycine, and that modification potentiates recombinant NMDA receptor currents. The modified channels remain open even after removing glutamate and glycine from the external solution. The degree of potentiation depends on the identity of the NR2 subunit (NR2A < NR2B < NR2C,D) inversely correlating with previous measurements of channel open probability. MTSEA-induced modification of channels is associated with increased glutamate potency, increased mean single-channel open time, and slightly decreased channel conductance. Modified channels are insensitive to the competitive antagonists D-2-amino-5-phosphonovaleric acid (APV) and 7-Cl-kynurenic acid, as well as allosteric modulators of gating (extracellular protons and Zn²⁺). However, channels remain fully sensitive to Mg²⁺ blockade and partially sensitive to pore block by (+)MK-801, (-)MK-801, ketamine, memantine, amantadine, and dextrorphan. The partial sensitivity to (+)MK-801 may reflect its ability to stimulate agonist unbinding from MT-SEA-modified receptors. In summary, these data suggest that the SYTANLAAF motif within M3 is a conserved and critical determinant of channel gating in all NMDA receptors.

Received for publication, December 17, 2004 , and in revised form, June 20, 2005.

^* This work was supported by grants from the NINDS, National Institutes of Health (to S. F. T.), National Alliance for Research on Schizophrenia and Depression (to S. F. T.), and the Howard Hughes Medical Institute (to K. E.). 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 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pharmacology, Emory University School of Medicine, Rollins Research Center, 1510 Clifton Rd., Atlanta, GA 30322-3090. Tel.: 404-727-1375; Fax: 404-727-0365; E-mail: hyuan{at}emory.edu.

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