Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites
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Brain Chemistry
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Cloning, Molecular
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Conotoxins / metabolism
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Conotoxins / pharmacology*
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Conus Snail
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Muscle Proteins / antagonists & inhibitors
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscle, Skeletal / chemistry
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Muscle, Skeletal / physiology
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NAV1.2 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Rats
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Sodium Channel Blockers / metabolism
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Sodium Channel Blockers / pharmacology*
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Sodium Channels / chemistry
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Sodium Channels / genetics
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Sodium Channels / metabolism*
Substances
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Conotoxins
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Muscle Proteins
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NAV1.2 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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Scn2A protein, rat
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Scn4a protein, rat
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Sodium Channel Blockers
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Sodium Channels
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muO-conotoxin MrVIA
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muO-conotoxin MrVIB