Pharmacological and biophysical characterization of a prokaryotic voltage-gated sodium channel

We have many ions in our body. Movement of ions in and out of cells mediates the generation of electrical signals in our nerves and heart, controlling the physiological processes like electrical signal transduction through our spine or regulating the normal heartbeat. Voltage-gated sodium channels are the main players of initiating and propagating this electrical stimulus, thereby any defects in these channels can lead to serious clinical conditions. Electrical rhythm disorders, such as epilepsy and arrhythmia, are treated with drugs that are made to inhibit hyperactive sodium channels. One of the proven drug targets of such clinical conditions are the non-conducting, inactivated sodium channels. However, we know little about the molecular mechanism of how sodium channels enter this non-conducting state, nor do we know where these drugs exactly bind to inhibit the uncontrolled activity of the sodium channels. The focus of my thesis is to understand the biophysical and pharmacological properties of voltage-gated sodium channel from bacteria that we have the structure of; with the hope that the structure-function understanding will be an asset to designing the next generation therapeutic agents that will acutely target the defective sodium channels. We also explore the conserved modulatory effects of sodium channel auxiliary subunits on the bacterial channel. Albeit the separation of millions of years between the evolution of mammals and bacteria, mammalian sodium channel auxiliary subunit altered the biophysical properties of the bacterial sodium channel, in a similar way to the mammalian channels. Continued research is needed to broaden our understanding of the voltage-gated sodium channels and its incredibly important roles in human physiology.