In vivo genetics of anaesthetic action H.A. Nash  British Journal of Anaesthesia  Volume 89, Issue 1, Pages 143-155 (July 2002) DOI: 10.1093/bja/aef159 Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 1 Anaesthetic sensitivity of wild-type and mutant nematodes. The dispersal index is fraction of animals that have migrated from the center of an agar plate to a food source at its edge. The potency with which volatile gaseous anaesthetics interfere with the coordinated movement of worms can be deduced from the plots of dispersal index versus anaesthetic concentration. For wild-type animals EC50 values for isoflurane and halothane are 0.74% and 0.45%, respectively. For the md130 mutants, the corresponding values are 4.36% and 1.29%. (Taken with permission from van Swinderen and colleagues.88) British Journal of Anaesthesia 2002 89, 143-155DOI: (10.1093/bja/aef159) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 2 Overview of mitochondrial oxidative metabolism. The 49 kDa subunit of Complex I that is encoded by the gas-1 gene is highlighted. Mutations in that gene depress flux of NADH through Conmplex I. This should result in depressed formation of ubiquinol, an important antioxidant, and depressed pumping of protons, the driving force for ATP synthesis. (Taken from Kayser and colleagues;38 permission to reproduce this figure has been sought from Anesthesiology.) British Journal of Anaesthesia 2002 89, 143-155DOI: (10.1093/bja/aef159) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 3 Conversion of guanine to compounds with neurobiological roles. The numbers indicate known enzymatic steps that might explain the consequences of white and brown mutations. These include intracellular transport of guanine by white/brown (1), synthesis of cGMP by guanylate cyclase (2), and conversion of GTP to tetrahydrobiopterin (3,4,6). The latter is a cofactor in the synthesis of several neuromodulators (7–9). (Taken from Campbell and Nash;10 permission to reproduce this figure has been sought from Journal of Neurobiology.) British Journal of Anaesthesia 2002 89, 143-155DOI: (10.1093/bja/aef159) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions

Fig 4 Neural pathways and anaesthesia mutations. In each diagram a behaviour that is assayed as an anaesthetic endpoint is depicted as dependent on one or more complex neural function. Each such function can in turn be dependent on neural pathways, some of which contain an anaesthetic target. It is also postulated that neural pathways that do not contain anaesthetic targets contribute to the complex neural function. Accordingly, mutations could alter anaesthetic sensitivity by affecting elements of either the anaesthetic-insensitive or the anaesthetic-sensitive pathways. For the latter, the mutations could be in a gene for the anaesthetic target or in a gene that otherwise affects the pathway. (a) There is only one anaesthetic target and it lies in a pathway that is essential for a particular behaviour. (b, c) There is more than one anaesthetic target that both lie in the same neural pathway (b) or lie in separate neural pathways (c). In either case, one can imagine scenarios where anaesthetic alteration of either target is sufficient to produce an anaesthetic endpoint. (See17 18 for an ongoing discussion of the relationship between the concentration of anaesthetic needed to produce half-maximal effects on each such target and the concentration needed to induce anaesthesia in half the population.) Alternatively, alteration of both targets might be required for anaesthesia. In the cases shown in b and c, respectively, this implies that a single neural function has redundant input from multiple pathways or that the assayed behaviour enjoys contributions from redundant neural functions. (Modified and expanded from Nash.61) British Journal of Anaesthesia 2002 89, 143-155DOI: (10.1093/bja/aef159) Copyright © 2002 British Journal of Anaesthesia Terms and Conditions