Trafficking Defective Mutations Modulate NaV1.5 N—Glycosylation States

Voltage gated sodium channels are membrane proteins that play a critical role in electrical signaling of excitable cells. Amongst this family, the isoform Nav1.5 is responsible for the initiation and propagation of cardiac action potentials. As most of membrane proteins, Nav1.5 is well known to be a glycoprotein with ∼5% of its total weight corresponding to carbohydrates. To date, it has been shown that Nav1.5 glycosylations such as sialylations influence biophysical properties of this channel protein. However, whereas N-glycosylation are well known post-traductional modifications that modulate surface localization of many ionic channels, little is known about these maturation impacts on voltage gated sodium channels. Perturbation of Nav1.5 trafficking is a well characterized phenomenon occurring in pathology such as Brugada syndrome. Our laboratory previously revealed that trafficking defective mutants of Nav1.5 exert a dominant negative effect upon wild type protein surface localization. The objective of this study was (i) to characterize N-glycosylations of Nav1.5 during its membrane trafficking and (ii) to investigate these maturations in the context of the dominant negative effect exerted by Nav1.5 trafficking defective mutations.