In excitable cells, voltage-gated Na+ channels initiate the action potential. In recent years, it has been discovered that these channels are composed of many parts to form a macromolecular signaling complex. These different parts precisely tune the function of Na+ channels to the cells that they reside in. This proposal aims to begin to discover mechanisms of how one component, the ?-subunits, modulate the function and pharmacology of Na+ channels. If the proposed aims succeed, this new understanding could provide a route to more effective and precisely-directed therapies for excitability disorders such as arrhythmia and epilepsy.

Public Health Relevance

The goal of this research is to discover how small molecules and proteins interact with ion channels in the heart to cause and prevent arrhythmias. To bridge the time and spatial scales involved, our approach is to characterize ion channel molecular motions experimentally and then to use this data to parameterize computer models that can predict their impact on the cell, tissue and organ level dynamics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL136553-01
Application #
9287719
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Balijepalli, Ravi C
Project Start
2017-04-01
Project End
2022-03-31
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Silva, Jonathan R (2018) How to Connect Cardiac Excitation to the Atomic Interactions of Ion Channels. Biophys J 114:259-266
Mangold, Kathryn E; Brumback, Brittany D; Angsutararux, Paweorn et al. (2017) Mechanisms and models of cardiac sodium channel inactivation. Channels (Austin) 11:517-533
Zhu, Wandi; Voelker, Taylor L; Varga, Zoltan et al. (2017) Mechanisms of noncovalent ? subunit regulation of NaV channel gating. J Gen Physiol :
Peters, Colin H; Yu, Alec; Zhu, Wandi et al. (2017) Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation. PLoS One 12:e0184605