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Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors

Author

Listed:
  • S. John Mihic

    (University of Colorado Health Sciences Center
    Alcohol Research Center, University of Colorado Health Sciences Center
    Bowman Gray School of Medicine of Wake Forest University)

  • Qing Ye

    (The University of Chicago)

  • Marilee J. Wick

    (University of Colorado Health Sciences Center
    Denver Veteran Administration Medical Center, Alcoholism Research Center)

  • Vladimir V. Koltchine

    (The University of Chicago)

  • Matthew D. Krasowski

    (The University of Chicago)

  • Suzanne E. Finn

    (The University of Chicago)

  • Maria Paola Mascia

    (University of Colorado Health Sciences Center)

  • C. Fernando Valenzuela

    (University of Colorado Health Sciences Center)

  • Kirsten K. Hanson

    (The University of Chicago)

  • Eric P. Greenblatt

    (University of Pennsylvania)

  • R. Adron Harris

    (University of Colorado Health Sciences Center
    Denver Veteran Administration Medical Center, Alcoholism Research Center
    The University of Chicago)

  • Neil L. Harrison

    (The University of Chicago
    The University of Chicago
    The University of Chicago)

Abstract

Volatile anaesthetics have historically been considered to act in a nonspecific manner on the central nervous system1,2. More recent studies, however, have revealed that the receptors for inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) and glycine are sensitive to clinically relevant concentrations of inhaled anaesthetics3. The function of GABAA and glycine receptors is enhanced by a number of anaesthetics4,5,6,7,8,9 and alcohols10,11,12, whereas activity of the related13 GABA ρ1 receptor is reduced14. We have used this difference in pharmacology to investigate the molecular basis for modulation of these receptors by anaesthetics and alcohols. By using chimaeric receptor constructs, we have identified a region of 45 amino-acid residues that is both necessary and sufficient for the enhancement of receptor function. Within this region, two specific amino-acid residues in transmembrane domains 2 and 3 are critical for allosteric modulation of both GABAA and glycine receptors by alcohols and two volatile anaesthetics. These observations support the idea that anaesthetics exert a specific effect on these ion-channel proteins, and allow for the future testing of specific hypotheses of the action of anaesthetics.

Suggested Citation

  • S. John Mihic & Qing Ye & Marilee J. Wick & Vladimir V. Koltchine & Matthew D. Krasowski & Suzanne E. Finn & Maria Paola Mascia & C. Fernando Valenzuela & Kirsten K. Hanson & Eric P. Greenblatt & R. A, 1997. "Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors," Nature, Nature, vol. 389(6649), pages 385-389, September.
    • Handle: RePEc:nat:nature:v:389:y:1997:i:6649:d:10.1038_38738
    DOI: 10.1038/38738
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    Cited by:

    1. Vernon A. Benignus & Philip J. Bushnell & William K. Boyes, 2005. "Toward Cost‐Benefit Analysis of Acute Behavioral Effects of Toluene in Humans," Risk Analysis, John Wiley & Sons, vol. 25(2), pages 447-456, April.
    2. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Toshikazu Sasabe & Shoichi Ishiura, 2010. "Alcoholism and Alternative Splicing of Candidate Genes," IJERPH, MDPI, vol. 7(4), pages 1-19, March.

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