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 (Na V ) channels: μ‐conotoxins block the pore, δ‐conotoxins inhibit channel inactivation, and μO‐conotoxins inhibit Na V channels by an unknown mechanism. The only currently known μO‐conotoxins MrVIA and MrVIB from Conus marmoreus were applied to cloned rat skeletal muscle (Na V 1.4) and brain (Na V 1.2) sodium channels in mammalian cells. A systematic domain‐swapping strategy identified the C‐terminal pore loop of domain‐3 as the major determinant for Na V 1.4 being more potently blocked than Na V 1.2 channels. μO‐conotoxins therefore show an interaction pattern with Na V channels that is clearly different from the related μ‐ and δ‐conotoxins, indicative of a distinct molecular mechanism of channel inhibition.