The muO-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 muO-conotoxins inhibit Na(V) channels by an unknown mechanism. The only currently known muO-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. muO-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.
Zorn
Stefan
S
Institute of Molecular Cell Biology, Research Unit Molecular and Cellular Biophysics, Medical Faculty of the Friedrich Schiller University Jena, Drackendorfer Str. 1, D-07747 Jena, Germany.
Leipold
Enrico
E
Hansel
Alfred
A
Bulaj
Grzegorz
G
Olivera
Baldomero M
BM
Terlau
Heinrich
H
Heinemann
Stefan H
SH
D000818:Animals; D001665:Binding Sites; D001923:Brain Chemistry; D003001:Cloning, Molecular; D020916:Conotoxins / Q000378:metabolism / Q000494:pharmacology*; D052078:Conus Snail; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000502:physiology; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051381:Rats; D026941:Sodium Channel Blockers / Q000378:metabolism / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D020916:Conotoxins; D009124:Muscle Proteins; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568253:Scn2A protein, rat; C466180:Scn4a protein, rat; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C094740:muO-conotoxin MrVIA; C094741:muO-conotoxin MrVIB