Lab of Molecular Biology, National Institute of Mental Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
We have reported that a component of the nervous system of Drosophila which lies upstream of the giant fiber and downstream of the photoreceptors is sensitive to volatile general anesthetics (M. Lin and H. A. Nash, PNAS, in press). The inhibitory effect of anesthetics on this component was studied by monitoring potentials that were evoked in muscle fibers innervated by the giant fiber in response to electrical stimulation through the eyes. In the absence of anesthetic, all flies respond to 0.5 Hz stimulation with perfect efficiency but this efficiency is progressively reduced as anesthetic concentration is increased. For halothane and several other anesthetics, the ED50 calculated from such experiments is within the range of values used in human patients. When this assay is applied to flies with a Shaker mutation, depending on the particular mutant tested, the ED50 of halothane is increased up to 6 fold. There is an excellent correlation for these alleles between the magnitude of the effect on anesthesia and the previously reported degree of inhibition of IA current. We have focused on one allele, ShKS133, which shows a large effect on halothane sensitivity. Genetic studies support the conclusion that the channel alteration is responsible for the halothane resistance of the ShKS133 strain. This mutant also is resistant to other general anesthetics, such as enflurane and methoxyflurane. The relation between results with Shaker mutants and results with har mutants as well as possible mechanisms for the Shaker effects will be addressed.