RT Journal Article
SR Electronic
T1 Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.18.389130
DO 10.1101/2020.11.18.389130
A1 Anna V. Elleman
A1 Gabrielle Devienne
A1 Christopher D. Makinson
A1 Allison L. Haynes
A1 John R. Huguenard
A1 J. Du Bois
YR 2020
UL http://biorxiv.org/content/early/2020/11/20/2020.11.18.389130.abstract
AB Here we report the pharmacologic blockade of voltage-gated sodium ion channels (NaV) by a synthetic saxitoxin derivative affixed to a photocleavable protecting group. We demonstrate that a functionalized saxitoxin (STX-eac) enables exquisite spatiotemporal control of NaV blockade to interrupt action potentials (APs) 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 AP propagation, with unmyelinated axons preferentially showing reduced AP fidelity under conditions of partial NaV blockade. These results validate STX-eac as a high precision tool for robust photocontrol of neuronal excitability and AP generation.Competing Interest StatementJustin Du Bois is a cofounder and holds equity shares in SiteOne Therapeutics, Inc., a start-up company interested in developing subtype-selective NaV modulators.