Document Type
Article
Language
eng
Publication Date
8-2012
Publisher
American Society for Biochemistry and Molecular Biology
Source Publication
Journal of Biological Chemistry
Source ISSN
0021-9258
Original Item ID
DOI: 10.1074/jbc.M111.338921
Abstract
The N-methyl-d-aspartate (NMDA) glutamate receptor is a major target of ethanol in the brain. Previous studies have identified positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN1 and GluN2A subunits that influence alcohol sensitivity. The predicted structure of the NMDA receptor, based on that of the related GluA2 subunit, indicates a close apposition of the alcohol-sensitive positions in M3 and M4 between the two subunit types. We tested the hypothesis that these positions interact to regulate receptor kinetics and ethanol sensitivity by using dual substitution mutants. In single-substitution mutants, we found that a position in both subunits adjacent to one previously identified, GluN1(Gly-638) and GluN2A(Phe-636), can strongly regulate ethanol sensitivity. Significant interactions affecting ethanol inhibition and receptor deactivation were observed at four pairs of positions in GluN1/GluN2A: Gly-638/Met-823, Phe-639/Leu-824, Met-818/Phe-636, and Leu-819/Phe-637; the latter pair also interacted with respect to desensitization. Two interactions involved a position in M4 of both subunits, GluN1(Met-818) and GluN2A(Leu-824), that does not by itself alter ethanol sensitivity, whereas a previously identified ethanol-sensitive position, GluN2A(Ala-825), did not unequivocally interact with any other position tested. These results also indicate a shift by one position of the predicted alignment of the GluN1 M4 domain. These findings have allowed for the refinement of the NMDA receptor M domain structure, demonstrate that this region can influence apparent agonist affinity, and support the existence of four sites of alcohol action on the NMDA receptor, each consisting of five amino acids at the M3-M4 domain intersubunit interfaces.
Recommended Citation
Ren, Hong; Zhao, Yulin; Dwyer, Donard S.; and Peoples, Robert W., "Interactions Among Positions in the Third and Fourth Membrane-Associated Domains at the Intersubunit Interface of the N-Methyl-D-Aspartate Receptor Forming Sites of Alcohol Action" (2012). Biomedical Sciences Faculty Research and Publications. 33.
https://epublications.marquette.edu/biomedsci_fac/33
Comments
Accepted version. Journal of Biological Chemistry, Vol. 287, No. 33 (June 2012): 27302-27312. DOI.
This research was originally published in the Journal of Biological Chemistry. Hong Ren, Yulin Zhao, Donald S. Dwyer and Robert W. Peoples. "Methyl-D-Aspartate Receptor Forming Sites of Alcohol Action." Journal of Biological Chemistry. 2012. Vol 33: 27302-37312. © the American Society for Biochemistry and Molecular Biology.