Voltage-activated sodium (Nav) channels are one the most widely targeted ion channel families by both commercially available drugs and toxins found in animal venoms. Their medical relevance is accentuated by mutations that underlie debilitating disorders such as pain syndromes, epilepsy, and cardiac arrhythmias. Despite their physiological importance, our understanding of these channels is hindered by a lack of insight into their complex working mechanisms. As opposed to existing as independent units, Nav channels are part of a signaling complex that involves an array of auxiliary proteins. My goal is to identify vital components within the Nav channel signaling complex and answer fundamental questions about their mechanisms of action at the molecular level. Successful completion of my aims will reveal the working mechanism of the overall Nav channel signaling complex in humans, help define Nav channel function in normal and disease states, and may lead to the discovery of novel strategies for developing therapeutics. To successfully achieve these goals, I will combine molecular biology with biochemical approaches and advanced electrophysiological techniques (mammalian cell/tissue recordings with the patch-clamp and cut- open techniques coupled to fluorescence detection). There could be no better choice than the laboratory of Dr. Bosmans at Johns Hopkins University School of Medicine since he has a well-equipped state-of-the-art research laboratory for studying ion channels. For this reason, the laboratory of Dr. Bosmans is the ideal environment to scientifically mature and to receive training in the technical skills that I aspire to make my own.
Voltage-gated sodium channels are members of an extensive signaling complex containing various auxiliary subunits. Not much is known about the interaction of voltage-gated sodium channels with these subunits but it is clear that they have an enormous impact on channel function. Our goal is to learn more about the complex effects of these components on voltage-gated sodium channel function and toxin pharmacology. Through accomplishing our aims, we will help define the working mechanism of the larger voltage-gated sodium channel signaling complex, an essential step towards our understanding of how we can target it with therapeutic drugs.
| Wingerd, Joshua S; Mozar, Christine A; Ussing, Christine A et al. (2017) The tarantula toxin ?/?-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity. Sci Rep 7:974 |
| Das, Samir; Gilchrist, John; Bosmans, Frank et al. (2016) Binary architecture of the Nav1.2-?2 signaling complex. Elife 5: |
| Osteen, Jeremiah D; Herzig, Volker; Gilchrist, John et al. (2016) Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain. Nature 534:494-9 |
| Gilchrist, John; Olivera, Baldomero M; Bosmans, Frank (2014) Animal toxins influence voltage-gated sodium channel function. Handb Exp Pharmacol 221:203-29 |
| Gilchrist, John; Das, Samir; Van Petegem, Filip et al. (2013) Crystallographic insights into sodium-channel modulation by the ?4 subunit. Proc Natl Acad Sci U S A 110:E5016-24 |
