In Project 5, we will investigate how anesthetic binding perturbs the mechanism of electromechanical coupling in anesthetic-sensitive, prototypical voltage-gated sodium and potassium channels.
Aim 1 concerns the prokaryotic Nav-channels NaChBac and NavAb possessing a dominant transmembrane domain.
Aim 2 concerns the eul

Public Health Relevance

The mechanisms of general anesthesia remain unresolved at the molecular level, greatly complicating the creation of new drugs designed to minimize multiple and serious side effects associated with available anesthetics. The fundamental understanding generated by accomplishing both Aims should provide a basis for the rational design of new drugs targeting the voltage sensor domain and/or the interface between the voltage sensor domain and the pore domain, instead of only the pore domain of Nav- and Kv-channels.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM055876-15
Application #
8740499
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
$294,862
Indirect Cost
$110,573
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Woll, Kellie A; Guzik-Lendrum, Stephanie; Bensel, Brandon M et al. (2018) An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules. J Biol Chem 293:11283-11295
Woll, Kellie A; Zhou, Xiaojuan; Bhanu, Natarajan V et al. (2018) Identification of binding sites contributing to volatile anesthetic effects on GABA type A receptors. FASEB J 32:4172-4189
Kasimova, Marina A; Yazici, Aysenur Torun; Yudin, Yevgen et al. (2018) A hypothetical molecular mechanism for TRPV1 activation that invokes rotation of an S6 asparagine. J Gen Physiol 150:1554-1566
Wang, Yali; Yang, Elaine; Wells, Marta M et al. (2018) Propofol inhibits the voltage-gated sodium channel NaChBac at multiple sites. J Gen Physiol 150:1317-1331
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
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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