Letters to Nature
Nature 389, 385-389 (25 September 1997) | doi:10.1038/38738; Received 27 February 1997; Accepted 1 August 1997
Sites of alcohol and volatile anaesthetic action on GABAA and glycine receptors
S. John Mihic1,2, Qing Ye3, Marilee J. Wick1,4, Vladimir V. Koltchine5, Matthew D. Krasowski6, Suzanne E. Finn3, Maria Paola Mascia1, C. Fernando Valenzuela1, Kirsten K. Hanson3, Eric P. Greenblatt7, R. Adron Harris1,4,5 & Neil L. Harrison3,5,6
- Department of Pharmacology, University of Colorado Health Sciences Center Denver, Colorado 80262, USA
- Present address: Department of Physiology and Pharmacology, Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, North Carolina 27157, USA
- Departments of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois 60637, USA
- Denver Veteran Administration Medical Center, Alcoholism Research Center, Denver, Colorado 80220, USA
- Departments of Pharmacological and Physiological Sciences, The University of Chicago, Chicago, Illinois 60637, USA
- Departments of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA
- Department of Anesthesia, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
- Alcohol Research Center, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA
Correspondence to: Neil L. Harrison3,5,6 Correspondence and requests for materials should be addressed to N.L.H. (e-mail: Email: nh17@midway.uchicago.edu).
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 
-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 
1 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.
