Role of protein domains in trafficking and localization of the voltage-gated sodium channel β2 subunit.

J Biol Chem

Cardiovascular Genetics Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Edifici IDIBGI, Salt, Province of Girona, Spain; Biomedical Research Networking Center on Cardiovascular Diseases (CIBERCV), Salt, Province of Girona, Spain; Department of Medical Sciences, University of Girona Medical School, Girona, Spain. Electronic address:

Published: November 2024

The voltage-gated sodium (Na) channel is critical for cardiomyocyte function since it is responsible for action potential initiation and its propagation throughout the cell. It consists of a protein complex made of a pore forming α subunit and associated β subunits, which regulate α subunit function and subcellular localization. We previously showed the implication of N-linked glycosylation and S-acylation of β2 in its polarized trafficking. Here, we present evidence of β2 dimerization. Moreover, we demonstrate the implication of the cytoplasmic tail, extracellular loop, and transmembrane domain on proper β2 folding and export to the cell surface of polarized Madin-Darby canine kidney cells. Substantial alteration, or lack of any of these domains, leads to accumulation of β2 in the endoplasmic reticulum, along with impaired complex N-glycosylation, which is needed for its efficient surface delivery. We also show that these alterations to β2 affected to a certain extent Na1.5 surface localization. Conversely, however, Na1.5 had little or no influence on β2 trafficking, its localization to the surface, or homodimer formation. Altogether, our data link the architecture of the β2 domains to the establishment of its proper subcellular localization. These findings could provide valuable insights to gain a deeper comprehension of the elusive biology of β subunits in excitable cells, such as neurons and cardiomyocytes.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532958PMC
http://dx.doi.org/10.1016/j.jbc.2024.107833DOI Listing

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