Abstract
The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Cells, Cultured
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Chromatography, High Pressure Liquid
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Chromatography, Reverse-Phase
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Ganglia, Spinal / cytology
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Ganglia, Spinal / metabolism
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HEK293 Cells
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Hippocampus / cytology
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Hippocampus / metabolism
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Humans
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Kinetics
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Membrane Potentials
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Mice
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Molecular Sequence Data
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NAV1.3 Voltage-Gated Sodium Channel / chemistry
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NAV1.3 Voltage-Gated Sodium Channel / genetics
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NAV1.3 Voltage-Gated Sodium Channel / metabolism*
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NAV1.5 Voltage-Gated Sodium Channel / chemistry
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NAV1.5 Voltage-Gated Sodium Channel / metabolism
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Patch-Clamp Techniques
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Protein Binding
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Protein Structure, Tertiary
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Rats
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Rats, Sprague-Dawley
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Sequence Alignment
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Sodium Channels / chemistry
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Sodium Channels / genetics
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Sodium Channels / metabolism*
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Spiders / metabolism
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Toxins, Biological / chemistry
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Toxins, Biological / isolation & purification
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Toxins, Biological / metabolism*
Substances
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NAV1.3 Voltage-Gated Sodium Channel
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NAV1.5 Voltage-Gated Sodium Channel
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SCN3A protein, human
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SCN5A protein, human
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Sodium Channels
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Toxins, Biological