Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
Anna V. Elleman, Gabrielle Devienne, Christopher D. Makinson, Allison L. Haynes, John R. Huguenard, J. Du Bois
Abstract
Abstract Here we report the pharmacologic blockade of voltage-gated sodium ion channels (Na V s) 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 V s 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 V s. 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.