Nature 385, 820 - 823 (27 February 1997); doi:10.1038/385820a0

Insensitivity to anaesthetic agents conferred by a class of GABA_A receptor subunit

Paul A. Davies^*, Mike C. Hanna, Tim G. Hales^* & Ewen F. Kirkness

The Institute for Genomic Research, 9712 Medical Center Drive, Rockville, Maryland 20850, USA
^*Department of Anesthesiology, Brain Research Institute, UCLA Medical Center, Los Angeles, California 90095, USA

A common feature of general anaesthetic agents is their ability to potentiate neuronal inhibition through GABA_A (-aminobutyric acid) receptors¹. At concentrations relevant to clinical anaesthesia, these agents cause a dramatic stimulation of the chloride currents that are evoked by the binding of the natural ligand, GABA_A. Although there is widespread evidence that the sensitivity of GABA_A receptors to anaesthetic agents is heterogeneous^2–4, the structural basis of these differences is largely unknown. Variations in subunit composition can have profound effects on the sensitivity of GABA_A receptors to modulatory agents such as benzodiazepines⁵. However, strict subunit specificity has not been demonstrated for the potentiating effects of anaesthetic agents^6–10. Here we describe a new class of human GABA_A receptor subunit () that can assemble with - and -subunits and confer an insensitivity to the potentiating effects of intravenous anaesthetic agents. The -subunit also abolishes the normal outward rectification of recombinant receptors in which it assembles. The expression pattern of this subunit in the brain suggests a new target for manipulation of neuronal pathways within the basal ganglia.

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