Abstract
Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaVs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaVs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of NaVs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to NaV-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial NaV block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.
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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Action Potentials / drug effects*
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Animals
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Axons / drug effects
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Axons / metabolism
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CHO Cells
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Cells, Cultured
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Corpus Callosum / cytology
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Corpus Callosum / drug effects
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Corpus Callosum / metabolism
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Cricetulus
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Embryo, Mammalian
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Female
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Hippocampus / cytology
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Male
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Mice
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NAV1.2 Voltage-Gated Sodium Channel / genetics
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NAV1.2 Voltage-Gated Sodium Channel / metabolism*
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Patch-Clamp Techniques
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Primary Cell Culture
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Rats
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Rats, Sprague-Dawley
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saxitoxin / analogs & derivatives
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Saxitoxin / pharmacology*
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Saxitoxin / radiation effects
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Single-Cell Analysis
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Spatio-Temporal Analysis
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Ultraviolet Rays
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Voltage-Gated Sodium Channel Blockers / pharmacology*
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Voltage-Gated Sodium Channel Blockers / radiation effects
Substances
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NAV1.2 Voltage-Gated Sodium Channel
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Recombinant Proteins
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Scn2A protein, rat
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Voltage-Gated Sodium Channel Blockers
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Saxitoxin