The μO-conotoxin MrVIA inhibits voltage-gated sodium channels by associating with domain-3

Several families of peptide toxins from cone snails affect voltage-gated sodium (NaV) channels: μ-conotoxins block the pore, δ-conotoxins inhibit channel inactivation, and μO-conotoxins inhibit NaV channels by an unknown mechanism. The only currently known μO-conotoxins MrVIA and MrVIB from Conus marmoreus were applied to cloned rat skeletal muscle (NaV1.4) and brain (NaV1.2) sodium channels in mammalian cells. A systematic domain-swapping strategy identified the C-terminal pore loop of domain-3 as the major determinant for NaV1.4 being more potently blocked than NaV1.2 channels. μO-conotoxins therefore show an interaction pattern with NaV channels that is clearly different from the related μ- and δ-conotoxins, indicative of a distinct molecular mechanism of channel inhibition.