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Full-Text Articles in Medicine and Health Sciences
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, Hong Ren, Yulin Zhao, Donard S. Dwyer, Robert W. Peoples
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, Hong Ren, Yulin Zhao, Donard S. Dwyer, Robert W. Peoples
Biomedical Sciences Faculty Research and Publications
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 …
Molecular Requirements For Ethanol Differential Allosteric Modulation Of Ligand-Gated Ion Channels Based On Selective G Beta Gamma Modulation, Gonzalo E. Yevenes, Gustavo Moraga-Cid, Ariel Avila, Leonardo Guzman, Maximiliano Figueroa, Robert W. Peoples, Luis G. Aguayo
Molecular Requirements For Ethanol Differential Allosteric Modulation Of Ligand-Gated Ion Channels Based On Selective G Beta Gamma Modulation, Gonzalo E. Yevenes, Gustavo Moraga-Cid, Ariel Avila, Leonardo Guzman, Maximiliano Figueroa, Robert W. Peoples, Luis G. Aguayo
Biomedical Sciences Faculty Research and Publications
It is now believed that the allosteric modulation produced by ethanol in glycine receptors (GlyRs) depends on alcohol binding to discrete sites within the protein structure. Thus, the differential ethanol sensitivity of diverse GlyR isoforms and mutants was explained by the presence of specific residues in putative alcohol pockets. Here, we demonstrate that ethanol sensitivity in two LGIC members, the GlyR adult alpha1 and embryonic alpha2 subunits, can be modified through selective mutations that rescued or impaired Gbetagamma modulation. Even though that both isoforms were able to physically interact with Gbetagamma, only the alpha1 GlyR was functionally modulated by Gbetagamma …
Pathologically Activated Neuroprotection Via Uncompetitive Blockade Of N-Methyl-D-Aspartate Receptors With Fast Off-Rate By Novel Multifunctional Dimer Bis(Propyl)-Cognitin, Jialie Luo, Wenming Li, Yuming Zhao, Hongjun Fu, Dik-Lung Ma, Jing Tang, Chaoying Li, Robert W. Peoples, Fushun Li, Qinwen Wang, Pingbo Huang, Jun Xia, Yuanping Pang, Yifan Han
Pathologically Activated Neuroprotection Via Uncompetitive Blockade Of N-Methyl-D-Aspartate Receptors With Fast Off-Rate By Novel Multifunctional Dimer Bis(Propyl)-Cognitin, Jialie Luo, Wenming Li, Yuming Zhao, Hongjun Fu, Dik-Lung Ma, Jing Tang, Chaoying Li, Robert W. Peoples, Fushun Li, Qinwen Wang, Pingbo Huang, Jun Xia, Yuanping Pang, Yifan Han
Biomedical Sciences Faculty Research and Publications
Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate …