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This Article Full Text Full Text (PDF) All Versions of this Article: 575/1/11    most recent jphysiol.2005.102756v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Keramidas, A. Articles by Harrison, N. L. Search for Related Content PubMed PubMed Citation Articles by Keramidas, A. Articles by Harrison, N. L. Related Collections Molecular and Genomic

¹ CV Starr Laboratory for Molecular Pharmacology, Department of Anesthesiology, Weill Medical College of Cornell University, New York, NY 10021, USA

The binding of the neurotransmitter GABA induces conformational changes in the GABA_A receptor (GABA_AR), 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 ß-10 strand (pre-M1 segment), which connects the extracellular domain to the transmembrane domain. In ₁ß_22s GABA_ARs, analysis of the 12 residues of the ß-10 strand in the ₁ subunit proximal to the first transmembrane domain identified two residues, ₁V212 and ₁K220, 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 ₁(K220A)ß_22s GABA_ARs and revealed that the macroscopic functional deficit in this mutant could be attributed to a slowing of the opening rate constant, from 1500 s^–1 in wild-type (WT) channels to 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 ₁(K220A)ß_22s channels. The ß-10 strand (pre-M1 segment) emerges, from this and other studies, as a key functional component in the activation of the GABA_AR.

(Received 4 May 2006; accepted after revision 7 June 2006; first published online 8 June 2006)
Corresponding author A Keramidas: CV Starr Laboratory for Molecular Pharmacology, Department of Anesthesiology, Weill Medical College, Cornell University, A-1040, 1300 York Avenue, New York, NY 10021, USA. Email: ank2013{at}med.cornell.edu

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