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

Here we report the pharmacologic blockade of voltage-gated sodium ion channels (Na_Vs) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of Na_Vs to interrupt action potentials in dissociated neurons and nerve fiber bundles. The photo-uncaged inhibitor (STX-ea) is a nanomolar potent, reversible binder of Na_Vs. We use STX-eac to reveal differential susceptibility of myelinated and unmyelinated axons in the corpus callosum to Na_V-dependent alterations in action potential propagation, with unmyelinated axons preferentially showing reduced action potential fidelity under conditions of partial Na_V block. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and action potential generation.