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: mu-conotoxins block the pore, delta-conotoxins inhibit channel inactivation, and mu O-conotoxins inhibit Na-V channels by an unknown mechanism. The only currently known mu O-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. mu O-conotoxins therefore show an interaction pattern with Na-V channels that is clearly different from the related mu- and delta-conotoxins, indicative of a distinct molecular mechanism of channel inhibition. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved