Voltage-gated sodium channels (Navs) are found in most excitable cells and are critical for initiating and propagating action potentials. These channels open to cause a large influx of Na+ ions in response to depolarization and almost instantaneously inactivate, leaving behind a small persistent current that is less than 1% of the peak current. Navs are tightly regulated by cellular processes and post-translational modifications (PTMs). One such PTM is the small ubiquitin-like modifier, SUMO1. SUMOylation is upregulated in hypoxia. We have shown that the cardiac subtype of Nav channels, Nav1.5, is found to be SUMOylated at the residue Lys442, causing pro-arrhythmic changes due to an in increase in the persistent late current of the channel. Closely related to Nav1.5 is the skeletal muscle subtype, Nav1.4. Variants of Nav1.4 are implicated in various types of muscular dystrophy. Due to the homology between Nav1.5 and Nav1.4, we hypothesized that SUMO1 also modulates Nav1.4 channel activity. We observed altered gating and function of Nav1.4 when the channel was co-expressed with SUMO1 and UBC9, the E1 ligase that facilitates SUMOylation. Determining how SUMO1 modifies the function of Nav1.4 and the identification of possible binding sites can contribute to a broader understanding of Nav1.4 regulation and open another area for therapeutic targets.
Scholl et al. (Sun,) studied this question.