Sebastian Casillas-Lopez
Pronouns: He/Him/Él
Research Mentor(s): Lori Isom
Research Mentor School/College/Department: Pharmacology / Medicine
Program:
Authors: Dyke McEwen, Sebastian Casillas-Lopez
Session: Session 5: 2:40 pm – 3:30 pm
Poster: 103
Abstract
ß1 is a member of the voltage-gated sodium channel (VGSC) family of proteins, including both a (Nav1.1-Nav1.9) and ß (ß1-ß4) subunits. It has been shown previously that the ß1 subunit has multiple functions including: regulating voltage-gated sodium channels (VGSC) and a-subunit cell surface density, acting as a cell adhesion molecule (CAM), and undergoing cleavage to initiate signal transduction pathways to regulate gene expression, neurite outgrowth, and other cellular processes. Abnormal expression of the SCN1B gene has been linked to disease pathologies, including epilepsy, cardiac arrhythmias, and cancer. One example resulting from mutations in SCN1B is Dravet syndrome, a devastating pediatric epileptic encephalopathy that is a significant risk factor associated with Sudden Unexpected Death in Epilepsy (SUDEP). The current study has been focused on attempting to visualize the intracellular domain (ICD) of ß1 through the utilization of Western blot, immunocytochemistry, immunoprecipitation, and other techniques, as well as investigating how the ICD translocates to the nucleus following cleavage in order to regulate gene expression. We have shown previously that ß1 undergoes regulated intramembrane proteolysis and can alter gene expression levels, particularly SCN1A, the gene encoding Nav1.1. However, it remains unclear what initiates the ß1 cleavage, where exactly it is cleaved, how the ICD translocates to the nucleus following cleavage, and what mechanisms contribute to its regulation of gene expression. Our preliminary data indicate that the ß1 ICD translocates to the nucleus via importin-a and importin-ß-mediated machinery. Pharmacologic inhibition of these proteins prevents ß1 ICD localization to the nuclear compartment. Future studies will further elucidate the exact mechanisms involved in ß1 ICD translocation and subsequent gene regulation.
