Free
Correspondence  |   October 2013
The Power of Unbiased Genetic Screens to Discover Novel Anesthetic Targets
Author Affiliations & Notes
  • (Accepted for publication July 5, 2013.)
    (Accepted for publication July 5, 2013.)×
Article Information
Correspondence
Correspondence   |   October 2013
The Power of Unbiased Genetic Screens to Discover Novel Anesthetic Targets
Anesthesiology 10 2013, Vol.119, 995-996. doi:10.1097/ALN.0b013e3182a4465c
Anesthesiology 10 2013, Vol.119, 995-996. doi:10.1097/ALN.0b013e3182a4465c
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.
sedensky@seattlechildrens.org, sedenm@uw.edu
References
Forman, SA The expanding genetic toolkit for exploring mechanisms of general anesthesia.. Anesthesiology. (2013). 118 769–71 [Article] [PubMed]
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 [Article] [PubMed]
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 [Article] [PubMed]
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 [Article] [PubMed]
Bayliss, DA, Barrett, PQ Emerging roles for two-pore-domain potassium channels and their potential therapeutic impact.. Trends Pharmacol Sci. (2008). 29 566–75 [Article] [PubMed]
Herring, BE, Xie, Z, Marks, J, Fox, AP Isoflurane inhibits the neurotransmitter release machinery.. J Neurophysiol. (2009). 102 1265–73 [Article] [PubMed]
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 [Article] [PubMed]