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• W3168657710 abstract "GABA type A receptors (GABAARs) belong to the pentameric ligand-gated ion channel (pLGIC) family and play a crucial role in mediating inhibition in the adult mammalian brain. Recently, a major progress in determining the static structure of GABAARs was achieved, although precise molecular scenarios underlying conformational transitions remain unclear. The ligand binding sites (LBSs) are located at the extracellular domain (ECD), very distant from the receptor gate at the channel pore. GABAAR gating is complex, comprising three major categories of transitions: openings/closings, preactivation, and desensitization. Interestingly, mutations at, e.g., the ligand binding site affect not only binding but often also more than one gating category, suggesting that structural determinants for distinct conformational transitions are shared. Gielen and co-workers (2015) proposed that the GABAAR desensitization gate is located at the second and third transmembrane segment. However, studies of our and others’ groups indicated that other parts of the GABAAR macromolecule might be involved in this process. In the present study, we asked how selected point mutations (β2G254V, α1G258V, α1L300V, and β2L296V) at the M2 and M3 transmembrane segments affect gating transitions of the α1β2γ2 GABAAR. Using high resolution macroscopic and single-channel recordings and analysis, we report that these substitutions, besides affecting desensitization, also profoundly altered openings/closings, having some minor effect on preactivation and agonist binding. Thus, the M2 and M3 segments primarily control late gating transitions of the receptor (desensitization, opening/closing), providing a further support for the concept of diffuse gating mechanisms for conformational transitions of GABAAR." @default.
• W3168657710 created "2021-06-22" @default.
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• W3168657710 date "2021-06-08" @default.
• W3168657710 modified "2023-09-30" @default.
• W3168657710 title "Mutations at the M2 and M3 Transmembrane Helices of the GABA_ARs α₁ and β₂ Subunits Affect Primarily Late Gating Transitions Including Opening/Closing and Desensitization" @default.
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• W3168657710 doi "https://doi.org/10.1021/acschemneuro.1c00151" @default.
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