Millions of patients receive general anesthesia in operating rooms around the world every year, and yet, the mechanisms underlying many actions of general anesthetics are not fully understood. Critically, general anesthetics lack selectivity and display the lowest therapeutic index. Thus, the morbidity and mortality associated with the use of general anesthetics is significant. This program project has gathered a strong team of biophysicist, chemists and structural biologists from various institutions (U. Penn., Thomas Jefferson U., Temple U., Drexel U. and U. Pitt.) to investigate the structural basis of general anesthesia with focus on membrane proteins involved in the initiation, propagation and transmission ofthe nerve impulse in the brain. Thus, by merging established and cutting-edge technologies, this project seeks to understand general anesthesia at the atomic level, and thereby facilitate the rational design of a new generation of more effective and safe general anesthetics. Xenopus laevis oocytes will be used to test the functional properties of the membrane proteins under investigation. This is a necessary step in the characterization of general anesthetic targets.

Public Health Relevance

Translating the functional relevance of the molecular data from the other projects to the in vivo condition requires characterization of electrical properties as an initial step. Project 2 provides that capability and expertise for studies in three natural ion channels with highly homologous mammalian counterparts. These results will allow extrapolation to intact cells, tissues and animals, and by connecting the molecular and in vivo effects, enable drug improvement in the future.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Program Projects (P01)
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Special Emphasis Panel (ZGM1-PPBC-5)
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University of Pennsylvania
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Loll, Patrick J (2018) Structural Analysis of Anesthetics in Complex with Soluble Proteins. Methods Enzymol 603:3-20
Yang, Elaine; Granata, Daniele; Eckenhoff, Roderic G et al. (2018) Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation. J Gen Physiol 150:1299-1316
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Bensel, Brandon M; Guzik-Lendrum, Stephanie; Masucci, Erin M et al. (2017) Common general anesthetic propofol impairs kinesin processivity. Proc Natl Acad Sci U S A 114:E4281-E4287
Okuno, Toshiaki; Koutsogiannaki, Sophia; Ohba, Mai et al. (2017) Intravenous anesthetic propofol binds to 5-lipoxygenase and attenuates leukotriene B4 production. FASEB J 31:1584-1594
Granata, Daniele; Ponzoni, Luca; Micheletti, Cristian et al. (2017) Patterns of coevolving amino acids unveil structural and dynamical domains. Proc Natl Acad Sci U S A 114:E10612-E10621
Carnevale, Vincenzo; Klein, Michael L (2017) Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol 43:156-162

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