biostudies-literaturePierce SROVPR Pilot/Seed Grants (OSU-CHS)Taylor Family Institute for Innovative Psychiatric ResearchNIHNIGMS NIH HHS698https://www.ebi.ac.uk/biostudies/studies/S-EPMC10135968biostudies-literatureUnknown13(4)The positive allosteric modulators (PAMs) of the α7 nicotinic receptor <i>N</i>-(5-Cl-2-hydroxyphenyl)-<i>N</i>'-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (<i>E</i>)-3-(furan-2-yl)-<i>N</i>-(<i>p</i>-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABA_A receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α-, α+/β-, and γ+/β-), as well as the orphan α+/γ- interface, modify receptor poteBiomoleculesMutational Analysis of Anesthetic Binding Sites and Their Effects on GABA_A Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor.PMC10135968R01GM108580R01 GM108580R35GM140947R35 GM140947Ortells MOGermann ALMenon SLPierce SRArias HRXu SQAkk GfalseMutational Analysis of Anesthetic Binding Sites and Their Effects on GABA_A Receptor Activation and Modulation by Positive Allosteric Modulators of the α7 Nicotinic Receptor.The positive allosteric modulators (PAMs) of the α7 nicotinic receptor <i>N</i>-(5-Cl-2-hydroxyphenyl)-<i>N</i>'-[2-Cl-5-(trifluoromethyl)phenyl]-urea (NS-1738) and (<i>E</i>)-3-(furan-2-yl)-<i>N</i>-(<i>p</i>-tolyl)-acrylamide (PAM-2) potentiate the α1β2γ2L GABA_A receptor through interactions with the classic anesthetic binding sites located at intersubunit interfaces in the transmembrane domain of the receptor. In the present study, we employed mutational analysis to investigate in detail the involvement and contributions made by the individual intersubunit interfaces to receptor modulation by NS-1738 and PAM-2. We show that mutations to each of the anesthetic-binding intersubunit interfaces (β+/α-, α+/β-, and γ+/β-), as well as the orphan α+/γ- interface, modify receptor pote2023-01-01T00:00:00Z2023 Apr2026-04-08T12:17:57.803Z2025-04-04T08:34:47.609ZS-EPMC101359683718944510.3390/biom13040698