ArticleBiophysical journal1999
Allosteric activation mechanism of the alpha 1 beta 2 gamma 2 gamma-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine.
Article in Biophysical journal, 1999. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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84 citing papers in PubMed, 140 citations in OpenAlex.
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- Electrophysiology of ionotropic GABA receptors.Cellular and molecular life sciences : CMLS · 2021Review
- A critical residue in the αeLife · 2021Article
- The desensitization pathway of GABANature communications · 2020Article
- Enhancement of Muscimol Binding and Gating by Allosteric Modulators of the GABAMolecular pharmacology · 2020Article
- Structural analysis of pathogenic missense mutations in GABRA2 and identification of a novel de novo variant in the desensitization gate.Molecular genetics & genomic medicine · 2020Article
- Steady-state activation and modulation of the synaptic-type α1β2γ2L GABAPhysiological reports · 2019Article
- Steady-State Activation and Modulation of the ConcatemericMolecular pharmacology · 2019Article
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24 more citing papers are in PubMed but not listed here.
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2 authors at 1 institution in 1 country.
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Abstract
A conserved leucine residue in the midpoint of the second transmembrane domain (M2) of the ligand-activated ion channel family has been proposed to play an important role in receptor activation. In this study, we assessed the importance of this leucine in the activation of rat alpha 1 beta 2 gamma 2 GABA receptors expressed in Xenopus laevis oocytes by site-directed mutagenesis and two-electrode voltage clamp. The hydrophobic conserved M2 leucines in alpha1(L263), beta2(L259), and gamma 2(L274) subunits were mutated to the hydrophilic amino acid residue serine and coexpressed in all possible combinations with their wild-type and/or mutant counterparts. The mutation in any one subunit decreased the EC(50) and created spontaneous openings that were blocked by picrotoxin and, surprisingly, by the competitive antagonist bicuculline. The magnitudes of the shifts in GABA EC(50) and picrotoxin IC(50) as well as the degree of spontaneous openings were all correlated with the number of subunits carrying the leucine mutation. Simultaneous mutation of the GABA binding site (beta 2Y157S; increased the EC(50)) and the conserved M2 leucine (beta 2L259S; decreased the EC(50)) produced receptors with the predicted intermediate agonist sensitivity, indicating the two mutations affect binding and gating independently. The results are discussed in light of a proposed allosteric activation mechanism.
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