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
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
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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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