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

SummaryHere 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.

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

Nature Communications ◽

10.1038/s41467-021-24392-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Anna V. Elleman ◽

Gabrielle Devienne ◽

Christopher D. Makinson ◽

Allison L. Haynes ◽

John R. Huguenard ◽

...

Keyword(s):

Action Potential ◽

Action Potentials ◽

Neuronal Excitability ◽

Differential Susceptibility ◽

Protecting Group ◽

Voltage Gated ◽

Unmyelinated Axons ◽

Voltage Gated Sodium Channels ◽

Sodium Ion Channels ◽

Spatiotemporal Control

AbstractHere 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.

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Nitrergic modulation of neuronal excitability in the mouse hippocampus is mediated via regulation of Kv2 and voltage‐gated sodium channels

Hippocampus ◽

10.1002/hipo.23366 ◽

2021 ◽

Author(s):

Hannah Scheiblich ◽

Joern R. Steinert

Keyword(s):

Sodium Channels ◽

Neuronal Excitability ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Mouse Hippocampus

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Rapidly Assaying Voltage-Gated Sodium Channels using Light-Induced Action Potentials and Fluorescent Recordings of the Membrane Potential in an Instrument with a Novel Detector Array

Biophysical Journal ◽

10.1016/j.bpj.2019.11.3145 ◽

2020 ◽

Vol 118 (3) ◽

pp. 579a

Author(s):

Joerg Oestreich ◽

Stephen S. Smith ◽

Jay Trautman ◽

Andrew L. Blatz

Keyword(s):

Membrane Potential ◽

Sodium Channels ◽

Action Potentials ◽

Detector Array ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Action Potentials and Na+ voltage-gated ion channels in Placozoa

10.1101/2020.08.09.243113 ◽

2020 ◽

Author(s):

Daria Y. Romanova ◽

Ivan V. Smirnov ◽

Mikhail A. Nikitin ◽

Andrea B. Kohn ◽

Alisa I. Borman ◽

...

Keyword(s):

Sodium Channels ◽

Action Potentials ◽

Parallel Evolution ◽

Cell Types ◽

List Type ◽

Behavioral Integration ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Invertebrate Animal ◽

Sodium Dependent

AbstractPlacozoa are small disc-shaped animals, representing the simplest known, possibly ancestral, organization of free-living animals. With only six morphological distinct cell types, without any recognized neurons or muscle, placozoans exhibit fast effector reactions and complex behaviors. However, little is known about electrogenic mechanisms in these animals. Here, we showed the presence of rapid action potentials in four species of placozoans (Trichoplax adhaerens [H1 haplotype], Trichoplax sp.[H2], Hoilungia hongkongensis [H13], and Hoilungia sp. [H4]). These action potentials are sodium-dependent and can be inducible. The molecular analysis suggests the presence of 5-7 different types of voltage-gated sodium channels, which showed substantial evolutionary radiation compared to many other metazoans. Such unexpected diversity of sodium channels in early-branched animal lineages reflect both duplication events and parallel evolution of unique behavioral integration in these nerveless animals.HighlightsPlacozoans are the simplest known animals without recognized neurons and musclesWith only six morphological cell types, placozoans showed complex & rapid behaviorsSodium-dependent action potentials have been discovered in intact animalsVoltage-gated sodium channels (Nav) in Placozoa support a rapid behavioral integrationPlacozoans have more Nav channels that any studied invertebrate animal so farDiversification of Nav-channels highlight the unique evolution of these nerveless animals

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Fibroblast Growth Factor Homologous Factors Control Neuronal Excitability through Modulation of Voltage-Gated Sodium Channels

Neuron ◽

10.1016/j.neuron.2007.07.006 ◽

2007 ◽

Vol 55 (3) ◽

pp. 449-463 ◽

Cited By ~ 134

Author(s):

Mitchell Goldfarb ◽

Jon Schoorlemmer ◽

Anthony Williams ◽

Shyam Diwakar ◽

Qing Wang ◽

...

Keyword(s):

Growth Factor ◽

Fibroblast Growth Factor ◽

Sodium Channels ◽

Neuronal Excitability ◽

Fibroblast Growth ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Faculty Opinions recommendation of Precise spatiotemporal control of voltage-gated sodium channels by photocaged saxitoxin.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.740445819.793587331 ◽

2021 ◽

Author(s):

James Trimmer

Keyword(s):

Sodium Channels ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Spatiotemporal Control

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Dehydrocrenatidine Inhibits Voltage-Gated Sodium Channels and Ameliorates Mechanic Allodia in a Rat Model of Neuropathic Pain

Toxins ◽

10.3390/toxins11040229 ◽

2019 ◽

Vol 11 (4) ◽

pp. 229 ◽

Cited By ~ 4

Author(s):

Fang Zhao ◽

Qinglian Tang ◽

Jian Xu ◽

Shuangyan Wang ◽

Shaoheng Li ◽

...

Keyword(s):

Neuropathic Pain ◽

Rat Model ◽

Analgesic Effect ◽

Neuronal Excitability ◽

Active Components ◽

Action Potential Firing ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Ic50 Values ◽

Medical Plant

Picrasma quassioides (D. Don) Benn, a medical plant, is used in clinic to treat inflammation, pain, sore throat, and eczema. The alkaloids are the main active components in P. quassioides. In this study, we examined the analgesic effect of dehydrocrenatidine (DHCT), a β-carboline alkaloid abundantly found in P. quassioides in a neuropathic pain rat model of a sciatic nerve chronic constriction injury. DHCT dose-dependently attenuated the mechanic allodynia. In acutely isolated dorsal root ganglion, DHCT completely suppressed the action potential firing. Further electrophysiological characterization demonstrated that DHCT suppressed both tetrodotoxin-resistant (TTX-R) and sensitive (TTX-S) voltage-gated sodium channel (VGSC) currents with IC50 values of 12.36 μM and 4.87 µM, respectively. DHCT shifted half-maximal voltage (V1/2) of inactivation to hyperpolarizing direction by ~16.7 mV in TTX-S VGSCs. In TTX-R VGSCs, DHCT shifted V1/2 of inactivation voltage to hyperpolarizing direction and V1/2 of activation voltage to more depolarizing potential by ~23.9 mV and ~12.2 mV, respectively. DHCT preferred to interact with an inactivated state of VGSCs and prolonged the repriming time in both TTX-S and TTX-R VGSCs, transiting the channels into a slow inactivated state from a fast inactivated state. Considered together, these data demonstrated that the analgesic effect of DHCT was likely though the inhibition of neuronal excitability.

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Assessment of the effect of etomidate on voltage-gated sodium channels and action potentials in rat primary sensory cortex pyramidal neurons

European Journal of Pharmacology ◽

10.1016/j.ejphar.2014.04.036 ◽

2014 ◽

Vol 736 ◽

pp. 55-62 ◽

Cited By ~ 10

Author(s):

Yu Zhang ◽

Jiong-ce He ◽

Xing-kui Liu ◽

Yi Zhang ◽

Yuan Wang ◽

...

Keyword(s):

Sodium Channels ◽

Action Potentials ◽

Pyramidal Neurons ◽

Sensory Cortex ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Primary Sensory Cortex

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Synthetic Approaches to Zetekitoxin AB, a Potent Voltage-Gated Sodium Channel Inhibitor

Marine Drugs ◽

10.3390/md18010024 ◽

2019 ◽

Vol 18 (1) ◽

pp. 24

Author(s):

Kanna Adachi ◽

Hayate Ishizuka ◽

Minami Odagi ◽

Kazuo Nagasawa

Keyword(s):

Total Synthesis ◽

Action Potentials ◽

Chemical Structure ◽

Potent Inhibitor ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Carbon Carbon Bond ◽

Biological Tool ◽

Shellfish Toxin ◽

Synthetic Approaches

Voltage-gated sodium channels (NaVs) are membrane proteins that are involved in the generation and propagation of action potentials in neurons. Recently, the structure of a complex made of a tetrodotoxin-sensitive (TTX-s) NaV subtype with saxitoxin (STX), a shellfish toxin, was determined. STX potently inhibits TTX-s NaV, and is used as a biological tool to investigate the function of NaVs. More than 50 analogs of STX have been isolated from nature. Among them, zetekitoxin AB (ZTX) has a distinctive chemical structure, and is the most potent inhibitor of NaVs, including tetrodotoxin-resistant (TTX-r) NaV. Despite intensive synthetic studies, total synthesis of ZTX has not yet been achieved. Here, we review recent efforts directed toward the total synthesis of ZTX, including syntheses of 11-saxitoxinethanoic acid (SEA), which is considered a useful synthetic model for ZTX, since it contains a key carbon–carbon bond at the C11 position.

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