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doi: 10.1097/ALN.0b013e3182a4465c

The Power of Unbiased Genetic Screens to Discover Novel Anesthetic Targets

Morgan, Phil G. M.D.; Sedensky, Margaret M. M.D.*

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To the Editor:

We are writing in response to Dr. Forman’s1 editorial “The Expanding Genetic Toolkit for Exploring Mechanisms of General Anesthesia” in the April issue of ANESTHESIOLOGY. Dr. Forman covers many excellent points about the use of genetics in understanding anesthetic mechanisms. However, we think that he has overlooked, and perhaps unintentionally discounted, the key ability of an unbiased forward genetic screen to study anesthetic action. A forward screen generates mutations randomly and then looks for those mutations that affect a particular trait. Its unique beauty or power is that it can discover novel mechanisms that would not be found if one presupposed to know an anesthetic target. Forward genetic screens have identified plausible possible targets of volatile anesthetics. They have included leak channels,2 neurotransmitter release machinery,3 and mitochondria.4 All three possibilities have been shown to be directly affected by volatile anesthetics and have been shown to affect anesthetic sensitivity in multiple organisms.5–7 By dismissing mitochondrial complex I as a possible anesthetic target, it seems that Dr. Forman does not appreciate the full power of a genetic approach to solve difficult problems.
Because to date no single target has been identified as both necessary and sufficient to produce the anesthetic state for most drugs and because more than one pathway contributes to the anesthesia state even for the same drug, other relevant targets clearly exist. The search for the mechanism of action of volatile anesthetics started many decades ago, and yet new targets are occasionally discovered and validated—why should we believe that we have discovered them all? Unbiased approaches such as forward genetics seem well suited to help discover these elusive remaining targets.
Phil G. Morgan, M.D., Margaret M. Sedensky, M.D.*
*Seattle Children’s Research Institute, University of Washington, Seattle, Washington. margaret.,
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1. Forman SA. The expanding genetic toolkit for exploring mechanisms of general anesthesia. Anesthesiology. 2013;118:769–71

2. Humphrey JA, Hamming KS, Thacker CM, Scott RL, Sedensky MM, Snutch TP, Morgan PG, Nash HA. A putative cation channel and its novel regulator: Cross-species conservation of effects on general anesthesia. Curr Biol. 2007;17:624–9

3. Hawasli AH, Saifee O, Liu C, Nonet ML, Crowder CM. Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release in Caenorhabditis elegans. Genetics. 2004;168:831–43

4. Kayser EB, Morgan PG, Sedensky MM. GAS-1: A mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. Anesthesiology. 1999;90:545–54

5. Bayliss DA, Barrett PQ. Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact. Trends Pharmacol Sci. 2008;29:566–75

6. Herring BE, Xie Z, Marks J, Fox AP. Isoflurane inhibits the neurotransmitter release machinery. J Neurophysiol. 2009;102:1265–73

7. Quintana A, Morgan PG, Kruse SE, Palmiter RD, Sedensky MM. Altered anesthetic sensitivity of mice lacking Ndufs4, a subunit of mitochondrial complex I. PLoS One. 2012;7:e42904

© 2013 American Society of Anesthesiologists, Inc.

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