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Molecular Pharmacology

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Research ArticleArticle

Benzodiazepines Induce a Conformational Change in the Region of the γ-Aminobutyric Acid Type A Receptor α1-Subunit M3 Membrane-Spanning Segment

Daniel B. Williams and Myles H. Akabas
Molecular Pharmacology November 2000, 58 (5) 1129-1136; DOI: https://doi.org/10.1124/mol.58.5.1129
Daniel B. Williams
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Myles H. Akabas
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Abstract

Benzodiazepine binding to γ-aminobutyric acid type A (GABAA) receptors allosterically modulates GABA binding and increases the currents induced by submaximal GABA concentrations. Benzodiazepines induce conformational changes in the GABA-binding site in the extracellular domain, but it is uncertain whether these conformational changes extend into the membrane-spanning domain where the channel gate is located. Alone, benzodiazepines do not open the channel. We used the substituted-cysteine-accessibility method to investigate diazepam-induced conformational changes in the region of the α1-subunit M3 membrane-spanning segment. In the absence of diazepam or GABA, pCMBS− did not react at a measurable rate with cysteine-substitution mutants between α1Phe296 and α1Glu303. In the presence of 100 nM diazepam, pCMBS− reacted with α1F296C, α1F298C, and α1L301C but not with the other cysteine mutants between α1Phe296 and α1Glu303. These three mutants are a subset of the five residues that we previously showed reacted with pCMBS− applied in the presence of GABA. The pCMBS− reaction rates with these three cysteine mutants were similar in the presence of diazepam and GABA. Thus, diazepam, which binds to the extracellular domain, induces a conformational change in the membrane-spanning domain that is similar to a portion of the change induced by GABA. Because diazepam does not open the channel, these results provide structural evidence that the diazepam-bound state represents an intermediate conformation distinct from the open and resting/closed states of the receptor. The diazepam-induced conformational change in the M3 segment vicinity may be related to the mechanism of allosteric potentiation.

Footnotes

    • Received April 27, 2000.
    • Accepted July 14, 2000.
  • Send reprint requests to: Dr. Myles Akabas, Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, New York 10461. E-mail:makabas{at}aecom.yu.edu

  • This work was supported in part by National Institutes of Health Grants NS30808, GM63266, and GM61925.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 58 (5)
Molecular Pharmacology
Vol. 58, Issue 5
1 Nov 2000
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Research ArticleArticle

Benzodiazepines Induce a Conformational Change in the Region of the γ-Aminobutyric Acid Type A Receptor α1-Subunit M3 Membrane-Spanning Segment

Daniel B. Williams and Myles H. Akabas
Molecular Pharmacology November 1, 2000, 58 (5) 1129-1136; DOI: https://doi.org/10.1124/mol.58.5.1129

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Research ArticleArticle

Benzodiazepines Induce a Conformational Change in the Region of the γ-Aminobutyric Acid Type A Receptor α1-Subunit M3 Membrane-Spanning Segment

Daniel B. Williams and Myles H. Akabas
Molecular Pharmacology November 1, 2000, 58 (5) 1129-1136; DOI: https://doi.org/10.1124/mol.58.5.1129
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