Different Sites of Alcohol Action in the NMDA Receptor GluN2A and GluN2B Subunits

Authors

Yulin Zhao, Marquette UniversityFollow
Hong Ren, Huazhong University of Science and TechnologyFollow
Donard S. Dwyer, Louisiana State University - ShreveportFollow
Robert W. Peoples, Marquette UniversityFollow

Document Type

Article

Language

eng

Format of Original

11 p.

Publication Date

2015

Publisher

Elsevier

Source Publication

Neuropharmacology

Source ISSN

1873-7064

Original Item ID

DOI: 10.1016/j.neuropharm.2015.05.018

Abstract

The NMDA receptor is a major target of alcohol action in the CNS, and recent behavioral and cellular studies have pointed to the importance of the GluN2B subunit in alcohol action. We and others have previously characterized four amino acid positions in the third and fourth membrane-associated (M) domains of the NMDA receptor GluN2A subunit that influence both ion channel gating and alcohol sensitivity. In this study, we found that substitution mutations at two of the four corresponding positions in the GluN2B subunit, F637 and G826, influence ethanol sensitivity and ion channel gating. Because position 826 contains a glycine residue in the native protein, we focused our attention on GluN2B(F637). Substitution mutations at GluN2B(F637) significantly altered ethanol IC₅₀ values, glutamate EC₅₀ values for peak (I_p) and steady-state (I_ss) current, and steady-state to peak current ratios (I_ss:I_p). Changes in apparent glutamate affinity were not due to agonist trapping in desensitized states, as glutamate I_ss EC₅₀ values were not correlated with I_ss:I_p values. Ethanol sensitivity was correlated with values of both I_p and I_ss glutamate EC₅₀, but not with I_ss:I_p. Values of ethanol IC₅₀, glutamate EC₅₀, and I_ss:I_p for mutants at GluN2B(F637) were highly correlated with the corresponding values for mutants at GluN2A(F636), consistent with similar functional roles of this position in both subunits. These results demonstrate that GluN2B(Phe637) regulates ethanol action and ion channel function of NMDA receptors. However, despite highly conserved M domain sequences, ethanol's actions on GluN2A and GluN2B subunits differ.

Comments

Accepted version. Neuropharmacology, Vol. 97 (2015): 240-250. DOI. © 2015 Elsevier Ltd. Used with permission.

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. 97 (2015): 240-250. DOI.

Recommended Citation

Zhao, Yulin; Ren, Hong; Dwyer, Donard S.; and Peoples, Robert W., "Different Sites of Alcohol Action in the NMDA Receptor GluN2A and GluN2B Subunits" (2015). Biological Sciences Faculty Research and Publications. 513.
https://epublications.marquette.edu/bio_fac/513