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. NARRATIVE 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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Cole, Alison E
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Wisconsin Madison
Schools of Medicine
United States
Zip Code
Goldschen-Ohm, Marcel P; Chanda, Baron (2014) Probing gating mechanisms of sodium channels using pore blockers. Handb Exp Pharmacol 221:183-201
Oelstrom, Kevin; Goldschen-Ohm, Marcel P; Holmgren, Miguel et al. (2014) Evolutionarily conserved intracellular gate of voltage-dependent sodium channels. Nat Commun 5:3420
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
Goldschen-Ohm, Marcel P; Capes, Deborah L; Oelstrom, Kevin M et al. (2013) Multiple pore conformations driven by asynchronous movements of voltage sensors in a eukaryotic sodium channel. Nat Commun 4:1350
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
Chowdhury, Sandipan; Chanda, Baron (2013) Free-energy relationships in ion channels activated by voltage and ligand. J Gen Physiol 141:11-28
Jarecki, Brian W; Makino, Shin-ichi; Beebe, Emily T et al. (2013) Function of Shaker potassium channels produced by cell-free translation upon injection into Xenopus oocytes. Sci Rep 3:1040
Chowdhury, Sandipan; Chanda, Baron (2012) Estimating the voltage-dependent free energy change of ion channels using the median voltage for activation. J Gen Physiol 139:3-17
Capes, Deborah L; Arcisio-Miranda, Manoel; Jarecki, Brian W et al. (2012) Gating transitions in the selectivity filter region of a sodium channel are coupled to the domain IV voltage sensor. Proc Natl Acad Sci U S A 109:2648-53
Arcisio-Miranda, Manoel; Muroi, Yukiko; Chowdhury, Sandipan et al. (2010) Molecular mechanism of allosteric modification of voltage-dependent sodium channels by local anesthetics. J Gen Physiol 136:541-54

Showing the most recent 10 out of 13 publications