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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM055876-15
Application #
8740495
Study Section
Special Emphasis Panel (ZGM1-PPBC-5)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
15
Fiscal Year
2014
Total Cost
$265,662
Indirect Cost
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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
Carnevale, Vincenzo; Klein, Michael L (2017) Small molecule modulation of voltage gated sodium channels. Curr Opin Struct Biol 43:156-162
Woll, Kellie A; Skinner, Kenneth A; Gianti, Eleonora et al. (2017) Sites Contributing to TRPA1 Activation by the Anesthetic Propofol Identified by Photoaffinity Labeling. Biophys J 113:2168-2172
Meng, Tao; Bu, Weiming; Ren, Xianfeng et al. (2016) Molecular mechanism of anesthetic-induced depression of myocardial contraction. FASEB J 30:2915-25
Woll, Kellie A; Murlidaran, Sruthi; Pinch, Benika J et al. (2016) A Novel Bifunctional Alkylphenol Anesthetic Allows Characterization of ?-Aminobutyric Acid, Type A (GABAA), Receptor Subunit Binding Selectivity in Synaptosomes. J Biol Chem 291:20473-86
Granata, Daniele; Carnevale, Vincenzo (2016) Accurate Estimation of the Intrinsic Dimension Using Graph Distances: Unraveling the Geometric Complexity of Datasets. Sci Rep 6:31377
Elokely, Khaled; Velisetty, Phanindra; Delemotte, Lucie et al. (2016) Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proc Natl Acad Sci U S A 113:E137-45
Woll, Kellie A; Dailey, William P; Brannigan, Grace et al. (2016) Shedding Light on Anesthetic Mechanisms: Application of Photoaffinity Ligands. Anesth Analg 123:1253-1262
Kinde, Monica N; Bondarenko, Vasyl; Granata, Daniele et al. (2016) Fluorine-19 NMR and computational quantification of isoflurane binding to the voltage-gated sodium channel NaChBac. Proc Natl Acad Sci U S A 113:13762-13767

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