The peptide toxin δ-hexatoxin-MrIX inhibits fast inactivation of Nas in mouse cerebellar granule cells.

Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (Nas). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of Nas in mouse cerebellar granule cells (CGCs) with an EC of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC Nas to the hyperpolarized direction. δ-hexatoxin-MrIX also acted on Na1.3 and Na1.4 channels heterologously expressed in HEK293T cells, as well as on Nas in acutely isolated cockroach DUM neurons. However, the Na1.5, Na1.7 and Na1.8 channels were resistant to δ-hexatoxin-MrIX. The toxin inhibited the fast inactivation of Na1.3 and Na1.4 with high affinity (EC values of 82.0 ± 3.0 nM and 24.0 ± 4.7 nM, respectively), but the saturating dose of toxin showed distinct efficacy on these two types of channels. δ-hexatoxin-MrIX is a peptide toxin acting on CGC Nas and could be used as a pharmacological tool to explore the role of Nas in granule cell maturation during cerebellum development.