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• W1865564547 endingPage "22" @default.
• W1865564547 startingPage "11" @default.
• W1865564547 abstract "The binding of the neurotransmitter GABA induces conformational changes in the GABAA receptor (GABAAR), leading to the opening of a gate that controls ion permeation through an integral transmembrane pore. A number of structural elements within each subunit, located near the membrane interface, are believed to undergo relative movements during this activation process. In this study, we explored the functional role of the beta-10 strand (pre-M1 segment), which connects the extracellular domain to the transmembrane domain. In alpha1beta2gamma2s GABAARs, analysis of the 12 residues of the beta-10 strand in the alpha1 subunit proximal to the first transmembrane domain identified two residues, alpha1V212 and alpha1K220, in which mutations produced rightward shifts in the GABA concentration-response relationship and also reduced the relative efficacy of the partial agonist, piperidine-4-sulphonic acid. Ultra-fast agonist techniques were applied to mutant alpha1(K220A)beta2gamma2s GABAARs and revealed that the macroscopic functional deficit in this mutant could be attributed to a slowing of the opening rate constant, from approximately 1500 s(-1) in wild-type (WT) channels to approximately 730 s(-1) in the mutant channels, and a reduction in the time spent in the active state for the mutant. These changes were accompanied by a decrease in agonist affinity, with half-maximal activation rates achieved at 0.77 mM GABA in WT and 1.4 mM GABA in the alpha1(K220A)beta2gamma2s channels. The beta-10 strand (pre-M1 segment) emerges, from this and other studies, as a key functional component in the activation of the GABAAR." @default.
• W1865564547 created "2016-06-24" @default.
• W1865564547 creator A5031542039 @default.
• W1865564547 creator A5042940621 @default.
• W1865564547 creator A5072148139 @default.
• W1865564547 date "2006-08-08" @default.
• W1865564547 modified "2023-10-18" @default.
• W1865564547 title "The pre‐M1 segment of the α1 subunit is a transduction element in the activation of the GABA_A receptor" @default.
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• W1865564547 doi "https://doi.org/10.1113/jphysiol.2005.102756" @default.
• W1865564547 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/1819431" @default.
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• W1865564547 hasPublicationYear "2006" @default.
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