Transmembrane segments prevent surface expression of sodium channel Nav1.8 and promote calnexin-dependent channel degradation

The research team led by Prof. Lan Bao from SIBCB recently discovered that transmembrane segments prevent surface expression of voltage-gated sodium channel (Nav) 1.8 and promote calnexin-dependent channel degradation. This finding was published in Journal of Biological Chemistry on October 18th.

 

The Nav1.8 contributes substantially to the rising phase of action potential in small dorsal root ganglion neurons. Nav1.8 is majorly localized intracellularly and its expression on the plasma membrane is regulated by exit from endoplasmic reticulum (ER). Previous work has identified an ER-retention/retrieval motif in the first intracellular loop of Nav1.8 which prevents its surface expression. While in this study, the researchers report that the transmembrane segments of Nav1.8 also cause this channel retained in the ER. Using transferrin receptor and CD8α as model molecules, immunocytochemistry showed that the first, second and third transmembrane segments in each domain of Nav1.8 reduced their surface expression. Alanine-scanning analysis revealed acidic amino acids as critical factors in the odd transmembrane segments. Furthermore, co-immunoprecipitation experiments showed that calnexin interacted with acidic amino acid-containing sequence through its transmembrane segment. Overexpression of calnexin resulted in increased degradation of those proteins through ER-associated degradation pathway, while downregulation of calnexin reversed the phenotype. Taken together, Prof. Bao’s results reveal a critical role and mechanism of transmembrane segments in surface expression and degradation of Nav1.8.

 

This work was supported by grants from the Ministry of Science and Technology of China and the National Natural Science Foundation of China.