The voltage-gated sodium (Nav) channel interactome consists of multiple interacting proteins including β-subunits, which are capable of modulating channel function and pharmacology. In this proposal, I intend to explore preliminary data suggesting that three new β-subunit homologues can modulate Nav channel function as part of the interactome. Like the four known β-subunits, these molecules consist of a V-type Immunoglobulin (Ig) extracellular domain and a short cytoplasmic C-terminal tail. However, knowledge of their biological role is scarce and primarily revolves around cellular interactions, a function that is possibly shared with β-subunits but requires further investigation. Thus, there is a need to examine the role of these Ig domain-containing molecules in the overall function of the Nav channel complex and investigate possible access of these subunits to the channel interactome to impact biophysical properties. Upon completion, this project will provide new insights in the Nav channel interactome and establish a baseline for future studies investigating Nav channel localization and clustering in excitable cell membranes.