Electrical signaling constitutes one of the primary means of communication in the central nervous system with the voltage-dependent sodium channels being responsible for initiating electrical impulses. Na+ channels exist in three functional states depending on transmembrane voltage: closed, open and inactivated. Mutations of Na+ channels that lead to incomplete inactivation has been linked to various disease conditions including congenital long QT syndrome, generalized epilepsy and muscle myotonia. Local anesthetics are a class of open channel blockers that are used to treat some channel-associated conditions and are believed to stabilize the channel in the inactivated state. The long term goal of my laboratory is to use structural approaches to understand the physical basis of gating of Na+ channels and their modulation. In this study, we propose to address a fundamental question: How do molecules like local anesthetics that bind to the channel pore modify the voltage-dependent gating behavior of ion channels. We will use fluorescence recordings of site-specific labels along with electrophysiological measurements to study the effect of local anesthetic on the conformational changes associated with voltage-sensing S4 segments of Na+ channels. We propose to study a) the effect of local anesthetic on the dynamics of individual S4 segments, b) the effect of local anesthetic on structure of the individual S4 segments, c) determine the molecular basis of coupling between S4 segments and local anesthetic binding at the pore, and d) determine if stabilizing the channel in the inactivated state favors local anesthetic binding. These experiments will be interpreted in light of the recently elucidated structure of a prototypical voltage-gated ion channel (Kv 1.2) to understand the structural basis of Na+ channel gating and its modulation by local anesthetics.
In order to develop better drugs to treat ion channel associated disease conditions, it becomes necessary to understand the structural underpinnings of ion channel function. The research proposed here utilizes a relatively novel structural approach to study the dynamics of the Na+ channel and its modulation by local anesthetics. This research will advance human health and well-being by contributing to the development of next generation of ion channel drugs that will modulate the channel function in a specified manner.
|Goldschen-Ohm, Marcel P; Klenchin, Vadim A; White, David S et al. (2016) Structure and dynamics underlying elementary ligand binding events in human pacemaking channels. Elife 5:|
|Bao, Huan; Goldschen-Ohm, Marcel; Jeggle, Pia et al. (2016) Exocytotic fusion pores are composed of both lipids and proteins. Nat Struct Mol Biol 23:67-73|
|Oelstrom, Kevin; Chanda, Baron (2016) Congruent pattern of accessibility identifies minimal pore gate in a non-symmetric voltage-gated sodium channel. Nat Commun 7:11608|
|Ahern, Christopher A; Payandeh, Jian; Bosmans, Frank et al. (2016) The hitchhiker's guide to the voltage-gated sodium channel galaxy. J Gen Physiol 147:1-24|
|Goldschen-Ohm, Marcel P; Chanda, Baron (2015) How to open a proton pore-more than S4? Nat Struct Mol Biol 22:277-8|
|Oelstrom, Kevin; Goldschen-Ohm, Marcel P; Holmgren, Miguel et al. (2014) Evolutionarily conserved intracellular gate of voltage-dependent sodium channels. Nat Commun 5:3420|
|Goldschen-Ohm, Marcel P; Chanda, Baron (2014) Probing gating mechanisms of sodium channels using pore blockers. Handb Exp Pharmacol 221:183-201|
|Chowdhury, Sandipan; Haehnel, Benjamin M; Chanda, Baron (2014) A self-consistent approach for determining pairwise interactions that underlie channel activation. J Gen Physiol 144:441-55|
|Capes, Deborah L; Goldschen-Ohm, Marcel P; Arcisio-Miranda, Manoel et al. (2013) Domain IV voltage-sensor movement is both sufficient and rate limiting for fast inactivation in sodium channels. J Gen Physiol 142:101-12|
|Jarecki, Brian W; Zheng, Suqing; Zhang, Leili et al. (2013) Tethered spectroscopic probes estimate dynamic distances with subnanometer resolution in voltage-dependent potassium channels. Biophys J 105:2724-32|
Showing the most recent 10 out of 20 publications