Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin

Nat Commun. 2021 Jul 7;12(1):4171. doi: 10.1038/s41467-021-24392-2.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Axons / drug effects
  • Axons / metabolism
  • CHO Cells
  • Cells, Cultured
  • Corpus Callosum / cytology
  • Corpus Callosum / drug effects
  • Corpus Callosum / metabolism
  • Cricetulus
  • Embryo, Mammalian
  • Female
  • Hippocampus / cytology
  • Male
  • Mice
  • NAV1.2 Voltage-Gated Sodium Channel / genetics
  • NAV1.2 Voltage-Gated Sodium Channel / metabolism*
  • Patch-Clamp Techniques
  • Primary Cell Culture
  • Rats
  • Rats, Sprague-Dawley
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Saxitoxin / analogs & derivatives
  • Saxitoxin / pharmacology*
  • Saxitoxin / radiation effects
  • Single-Cell Analysis
  • Spatio-Temporal Analysis
  • Ultraviolet Rays
  • Voltage-Gated Sodium Channel Blockers / pharmacology*
  • Voltage-Gated Sodium Channel Blockers / radiation effects

Substances

  • NAV1.2 Voltage-Gated Sodium Channel
  • Recombinant Proteins
  • Scn2A protein, rat
  • Voltage-Gated Sodium Channel Blockers
  • Saxitoxin