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Intersubunit Interactions At Putative Sites Of Ethanol Action In The M3 And M4 Domains Of The Nmda Receptor Glun1 And Glun2b Subunits, Robert W. Peoples, Hong Ren, Yulin Zhao

Biomedical Sciences Faculty Research and Publications

Background and Purpose: The N-methyl-D-aspartate (NMDA) receptor is an important target of alcohol action in the brain. Recent studies in this laboratory have demonstrated that alcohol-sensitive positions in the intersubunit interfaces of the M3 and M4 domains of GluN1 and GluN2A subunits interact with respect to ethanol sensitivity and receptor kinetics, and that alcohol-sensitive positions in the M domains of GluN2A and GluN2B subunits differ. In this study we tested for interactions among alcohol-sensitive positions at the M domain intersubunit interfaces in GluN1/GluN2B NMDA receptors.

Experimental Approach: We used whole-cell patch-clamp recording in tsA201 cells expressing tryptophan substitution mutants at …

Sites Of Alcohol Action At The Glun1/Glun2b Nmda Receptor M3-M4 Domain Intersubunit Interfaces, Yuanhao Zhao, M. Wu, Hong Ren, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

The N-methyl-D-aspartate (NMDA) receptor has been shown to be one of the most important target sites of alcohol in the central nervous system. We and others have identified positions in the third and fourth membrane-associated (M) domains of both GluN1 and GluN2A subunits that influence alcohol sensitivity. In the structural model of the NMDA receptor based upon the related GluA2 receptor, the outward face of the M3 domain of one subunit type is oriented toward the M4 domain of the other subunit type. We recently reported that four pairs of alcohol-sensitive amino acid positions in GluN1/GluN2A NMDA receptors interact at …

Differential Actions Of Ethanol And Trichloroethanol At Sites In The M3 And M4 Domains Of The Nmda Receptor Glun2a (Nr2a) Subunit, Ak Salous, H Ren, Ka Lamb, Xiang-Qun Hu, Rh Lipsky, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

Background and purpose:  Alcohol produces its behavioural effects in part due to inhibition of N-methyl-d-aspartate (NMDA) receptors in the CNS. Previous studies have identified amino acid residues in membrane-associated domains 3 (M3) and 4 (M4) of the NMDA receptor that influence ethanol sensitivity. In addition, in other alcohol-sensitive ion channels, sedative-hypnotic agents have in some cases been shown to act at sites distinct from the sites of ethanol action. In this study, we compared the influence of mutations at these sites on sensitivity to ethanol and trichloroethanol, a sedative-hypnotic agent that is a structural analogue of ethanol.

Experimental approach: …

Mutations At F637 In The Nmda Receptor Nr2a Subunit M3 Domain Influence Agonist Potency, Ion Channel Gating And Alcohol Action, H. Ren, Ak Salous, J. M. Paul, Rh Lipsky, Robert W. Peoples

Biomedical Sciences Faculty Research and Publications

Background and purpose:

NMDA receptors are important molecular targets of ethanol action in the CNS. Previous studies have identified a site in membrane-associated domain 3 (M3) of the NR1 subunit and two sites in M4 of the NR2A subunit that influence alcohol action; the sites in NR2A M4 also regulate ion channel gating. The purpose of this study was to determine whether mutations at the site in the NR2A subunit corresponding to the NR1 M3 site influence alcohol action and ion channel gating.

Experimental approach:

We investigated the effects of mutations at phenylalanine (F) 637 of the NR2A subunit using …