Document Type
Article
Language
eng
Publication Date
3-2017
Publisher
Elsevier
Source Publication
Neuropharmacology
Source ISSN
1873-7064
Original Item ID
DOI: 10.1016/j.neuropharm.2016.11.013
Abstract
The N-methyl-d-aspartate (NMDA) receptor is a key target of ethanol action in the central nervous system. Alcohol inhibition of NMDA receptor function involves small clusters of residues in the third and fourth membrane-associated (M) domains. Previous results from this laboratory have shown that two adjacent positions in the M3 domain, F636 and F637, can powerfully regulate alcohol sensitivity and ion channel gating. In this study, we report that these positions interact with one another in the regulation of both NMDA receptor gating and alcohol action. Using dual mutant cycle analysis, we detected interactions among various substitution mutants at these positions with respect to regulation of glutamate EC50, steady-state to peak current ratios (Iss:Ip), mean open time, and ethanol IC50. This interaction apparently involves a balancing of forces on the M3 helix, such that the disruption of function due to a substitution at one position can be reversed by a similar substitution at the other position. For example, tryptophan substitution at F636 or F637 increased or decreased channel mean open time, respectively, but tryptophan substitution at both positions did not alter open time. Interestingly, the effects of a number of mutations on receptor kinetics and ethanol sensitivity appeared to depend upon subtle structural differences, such as those between the isomeric amino acids leucine and isoleucine, as they could not be explained on the basis of sidechain molecular volume or hydrophilicity.
Recommended Citation
Ren, Hong; Zhao, Yulin; Wu, Man; Dwyer, Donard S.; and Peoples, Robert W., "Two Adjacent Phenylalanines In the NMDA Receptor GluN2A Subunit M3 Domain Interactively Regulate Alcohol Sensitivity and Ion Channel Gating" (2017). Biological Sciences Faculty Research and Publications. 533.
https://epublications.marquette.edu/bio_fac/533
Comments
NOTICE: this is the author’s version of a work that was accepted for publication in Neuropharmacology. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Neuropharmacology, Vol. 114 (March 1, 2017): pgs. 20-33. DOI. © 2017 Elsevier. Used with permission.