Role of SCN2A Polymorphism in Regulating Nav1.2 Brain Voltage Gated Sodium Channel

The SCN2A gene encodes the type II voltage-gated sodium channel alpha subunit. SCN2A mutations have increasingly been recognized to cause severe disorders including epilepsy, autism, and other neurological issues. Voltage gated sodium channels are crucial for the transmission of action potentials throughout the nervous system. These channels, specifically the Nav1.2 channel, have shown to play a central role in disorders such as epilepsy. Since rare mutations in the SCN2A gene have known to be the cause of these disorders, the functional consequences of more common variants may also have physiological significance. The Arg28Cys polymorphism is the 6th most common variant in the SCN2A gene (gnomAD database). The hypothesis of our research is that the Arg28Cys polymorphism alters the Nav1.2 channel by enhancing palmitoylation of the N-terminus. If the Nav1.2 channel N-terminus is palmitoylated, it should become more closely associated with cell membrane. We predict that enhancing membrane association of the Nav1.2 channel N-terminus alter channel properties and have an impact on the neuronal excitability. To test this, Xenopus oocytes are injected with mRNA coding for wild-type Nav1.2 and the Arg28Cys containing channel. Our next step is to use whole-cell electrophysiology and pharmacological manipulations to help determine if any observed functional alterations with the Arg28Cys mutant are dependent on palmitoylation.