Abstract
The SCN5A gene encodes the human cardiac sodium channel NaV1.5, essential for cardiac excitability and action potential propagation. Mutations in SCN5A are linked to various cardiac disorders, including Brugada Syndrome (BrS), typically leading to channel loss-of-function. Understanding alterations in NaV1.5 expression and sodium current density is vital for comprehending arrhythmogenesis and formulating therapeutic strategies. Post-translational modifications, especially sialylation, significantly impact channel functionality. We previously demonstrated that BrS patients show decreased protein sialylation, correlating with reduced sodium channel activity. This study aimed to investigate sialic acid's role in regulating NaV1.5 activity, testing if sialylation induction via mannosamine (ManNAc) supplementation could restore channel activity in-vitro. Preliminary tests with exogenous sialidases and ManNAc supplementation affirmed our hypothesis. We examined ManNAc's effect on NaV1.5 mutants common in BrS, which typically exhibit partial functional loss. We overexpressed mutations p.A344S, p.K1479A, and p.G1406R in HEK293A cells and measured sodium currents before and after ManNAc supplementation to stimulate sialic acid synthesis. ManNAc effectively restored sodium currents in mutants with intracellular and extracellular loop mutations. However, the p.1406G>A mutant, affecting the pore structure, showed no improvement, suggesting that sialic acid mainly influences channel membrane trafficking rather than direct glycosylation. This underscores the complexity of sialic acid's role and points to trafficking pathways as potential therapeutic targets. Notably, the treatment neither increased nor decreased sodium currents in wild-type NaV1.5 channels or in the CaV3.2 calcium channel, underscoring its specificity. In summary, our findings demonstrate that ManNAc supplementation can selectively restore the function of certain NaV1.5 mutants without affecting wild-type channels, highlighting the potential of targeting sialylation pathways for SCN5A-related arrhythmia treatments. Future research should aim to unravel these mechanisms further, providing insights into novel treatments for SCN5A-related arrhythmias.
Published Version
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