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 () and J. Bois ()
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Anna V. Elleman: Stanford University
Gabrielle Devienne: Stanford University School of Medicine
Christopher D. Makinson: Stanford University School of Medicine
Allison L. Haynes: Stanford University
John R. Huguenard: Stanford University School of Medicine
J. Bois: Stanford University

Nature Communications, 2021, vol. 12, issue 1, 1-9

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24392-2

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