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Research ArticleArticle

A State-Dependent Salt-Bridge Interaction Exists across the β/α Intersubunit Interface of the GABAA Receptor

Kurt T. Laha and David A. Wagner
Molecular Pharmacology April 2011, 79 (4) 662-671; DOI: https://doi.org/10.1124/mol.110.068619
Kurt T. Laha
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David A. Wagner
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Abstract

The GABAA receptor is a multisubunit protein that transduces the binding of a neurotransmitter at an intersubunit interface into the opening of a central ion channel. The structural components that mediate the steps involved in this action are poorly defined. A large amount of work has focused on clarifying the specific functions and interactions of residues believed to surround the GABA binding pocket. Here, we explored two charged residues (β2Asp163 and α1Arg120), which have been suggested by homology models to participate in a salt-bridge interaction. When mutated to alanine, both single mutants, as well as the double mutant, increase EC50-GABA, decrease the GABA binding rate, and accelerate deactivation and GABA unbinding rates. Double-mutant cycle analysis demonstrates that the effects of each alanine mutation on the GABA binding rate were additive and independent. In contrast, a significant coupling energy was found during an analysis of deactivation time constants. Using kinetic modeling, we further demonstrated that the GABA unbinding rates, in particular, are strongly coupled. These data suggest that β2Asp163 and α1Arg120 form a state-dependent salt bridge, interacting when GABA is bound to the receptor but not when the receptor is in the unbound state.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • This research was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke [Grant NS055793].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.068619.

  • ABBREVIATIONS:

    LGIC
    ligand-gated ion channel
    SCAM
    substituted cysteine accessibility method
    HEK
    human embryonic kidney
    SR-95531
    6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid hydrobromide
    ANOVA
    analysis of variance
    5-HT
    serotonin.

  • Received September 9, 2010.
  • Accepted December 16, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

A State-Dependent Salt-Bridge Interaction Exists across the β/α Intersubunit Interface of the GABAA Receptor

Kurt T. Laha and David A. Wagner
Molecular Pharmacology April 1, 2011, 79 (4) 662-671; DOI: https://doi.org/10.1124/mol.110.068619

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Research ArticleArticle

A State-Dependent Salt-Bridge Interaction Exists across the β/α Intersubunit Interface of the GABAA Receptor

Kurt T. Laha and David A. Wagner
Molecular Pharmacology April 1, 2011, 79 (4) 662-671; DOI: https://doi.org/10.1124/mol.110.068619
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