Despite the ubiquitous use of general anesthetics, the molecular basis of general anesthesia has yet to be elucidated. The long-term goal of this study is to shed light on the molecular basis of general anesthetic action, which may open novel opportunities to design safer general anesthetics. General anesthetics are thought to act on the central nervous system by directly interacting with membrane proteins. Since ion channels are the essence of electrical excitability in the nervous system, they are considered particularly relevant targets of general anesthetics. The central hypothesis of this proposal is that inhaled general anesthetics interact with discrete hydrophobic cavities and exert their physiological effects through allosteric coupling with an effector site involving the gating machinery of voltage-gated ion channels. This proposal investigates NaChBac, a bacterial homolog of mammalian voltage-gated sodium (Nav) channels, to characterize inhaled anesthetic interactions with voltage gated sodium channels.
The aims of this project are 1) to investigate the contributions of the S4-S5 linker and the S6 segment to inhaled anesthetic action in a voltage-gated sodium, channel, and 2) to investigate the structural basis of inhaled anesthetic action in a voltage-gated sodium channel. To pursue these aims a combination of mutagenesis, patch-clamp electrophysiology, protein biochemistry, anesthetic photolabeling and molecular dynamics simulations will be used. This work will provide a stepping-stone to similar investigations of mammalian Nav channels, which are also modulated by relevant doses of inhaled anesthetics and open the door to mechanistic studies of anesthetic effects on Nav channels.

Public Health Relevance

Efforts to limit the side effects and mortality of general anesthesia focus on constant monitoring during and after anesthesia to ensure patient safety. However, despite the refinement of monitoring strategies, morbidity and mortality associated with general anesthesia are still of clinical concern. The goal of this study is to shed light on the molecular basis of general anesthesia, which is a stepping-stone to the rational design of safer anesthetics for clinical use.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS077689-02
Application #
8402063
Study Section
Special Emphasis Panel (ZRG1-F03B-G (20))
Program Officer
Silberberg, Shai D
Project Start
2012-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
2
Fiscal Year
2013
Total Cost
$42,232
Indirect Cost
Name
Thomas Jefferson University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107