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.
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.
| 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 |
