NaV1.1 contributes to the cell cycle of human mesenchymal stem cells by regulating AKT and CDK2.

Non-excitable cells express sodium voltage-gated channel alpha subunit 1 gene and protein (SCN1A/NaV1.1); however, the functions of NaV1.1 are unclear. SCN1A was expressed in human mesenchymal stem cells (MSCs). Nav1.1 was abundantly expressed in the endoplasmic reticulum of MSCs; however, its expression was not found to be related to sodium currents. SCN1A-silencing reduced MSC proliferation and delayed the cell cycle in the S phase. SCN1A-silencing also suppressed the protein levels of CDK2 and AKT, despite similar mRNA expression, and inhibited AKT phosphorylation in MSCs. Cycloheximide-chase assay showed that SCN1A-silencing induced CDK2 but not AKT protein degradation in MSCs. Proteolysis inhibition assay using epoxomicin, bafilomycin A1, and NH4Cl, revealed that the ubiquitin-proteasome and autophagy/endo-lysosome systems were irrelevant to CDK2 and AKT protein reduction in SCN1A-silenced MSCs. AKT inhibitor LY294002 did not affect the degradation and nuclear localization of CDK2 in MSCs. Likewise, AKT activator SC79 did not attenuate the SCN1A-silencing effects on CDK2 in MSCs. These results suggest that NaV1.1 contributes to the cell cycle of MSCs by regulating the post-translational control of AKT and CDK2.