Poneratoxin as a key tool for investigating the relationship between sodium channel hypersensitivity and impaired nerve cell function.

Poneratoxin (PoTX) is a 25-residue peptide derived from the venom of bullet ant, Paraponera clavata, recognized for its potent activation of Na(V) channel and pain-inducing effects in murine models. In this study, for the first time, we conducted the evaluation of the excitotoxicity of PoTX and performed an in-depth analysis of transcriptomics and proteomics in vitro to elucidate its impact on the nervous system and underlying pharmacological mechanisms. Our results demonstrated that PoTX significantly induced calcium accumulation in SH-SY5Y cell model. Transcriptomic and proteomic analyses revealed that PoTX treatment led to cell cycle arrest, reduced neuronal plasticity, and accelerated cellular senescence. Additionally, PoTX significantly increased tau protein phosphorylation and aggregation via PI3K-Akt-mediated activation of GSK-3 and upregulation of CDK5. It also impaired autophagy by inhibiting ULK1 expression and activity, while concurrently downregulating multiple proteins associated with neuronal excitability. Given these findings and the high tolerance of nerve cells to PoTX treatment alone, along with its potent and sustained activation of Na(V) channels, PoTX may serve as a valuable tool for investigating the pharmacological relationship between hypersensitivity of Na(V) channels and the progression of neurological disorders, thereby facilitating the identification of potential therapeutic targets and corresponding drug development.