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 #
2P01GM055876-14A1
Application #
8534429
Study Section
Special Emphasis Panel (ZGM1-PPBC-5 (AN))
Project Start
Project End
2018-05-31
Budget Start
2013-09-26
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$296,034
Indirect Cost
$111,745
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Weiser, Brian P; Bu, Weiming; Wong, David et al. (2014) Sites and functional consequence of VDAC-alkylphenol anesthetic interactions. FEBS Lett 588:4398-403
Bu, Weiming; Pereira, Luis M; Eckenhoff, Roderic G et al. (2014) Stereoselectivity of isoflurane in adhesion molecule leukocyte function-associated antigen-1. PLoS One 9:e96649
Hénin, Jérôme; Salari, Reza; Murlidaran, Sruthi et al. (2014) A predicted binding site for cholesterol on the GABAA receptor. Biophys J 106:1938-49
Tronin, Andrey Y; Nordgren, C Erik; Strzalka, Joseph W et al. (2014) Direct evidence of conformational changes associated with voltage gating in a voltage sensor protein by time-resolved X-ray/neutron interferometry. Langmuir 30:4784-96
Chiara, David C; Gill, Jonathan F; Chen, Qiang et al. (2014) Photoaffinity labeling the propofol binding site in GLIC. Biochemistry 53:135-42
Palovcak, Eugene; Delemotte, Lucie; Klein, Michael L et al. (2014) Evolutionary imprint of activation: the design principles of VSDs. J Gen Physiol 143:145-56
Weiser, Brian P; Salari, Reza; Eckenhoff, Roderic G et al. (2014) Computational investigation of cholesterol binding sites on mitochondrial VDAC. J Phys Chem B 118:9852-60
Weiser, Brian P; Woll, Kellie A; Dailey, William P et al. (2014) Mechanisms revealed through general anesthetic photolabeling. Curr Anesthesiol Rep 4:57-66
Yuki, Koichi; Bu, Weiming; Xi, Jin et al. (2013) Propofol shares the binding site with isoflurane and sevoflurane on leukocyte function-associated antigen-1. Anesth Analg 117:803-11
Raju, S G; Barber, Annika F; LeBard, David N et al. (2013) Exploring volatile general anesthetic binding to a closed membrane-bound bacterial voltage-gated sodium channel via computation. PLoS Comput Biol 9:e1003090

Showing the most recent 10 out of 36 publications