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

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.

Download Full-text

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

Download Full-text

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

Download Full-text

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

Download Full-text

Isolation and Structure-Activity of μ-Conotoxin TIIIA, A Potent Inhibitor of Tetrodotoxin-Sensitive Voltage-Gated Sodium Channels

Molecular Pharmacology ◽

10.1124/mol.106.028225 ◽

2006 ◽

Vol 71 (3) ◽

pp. 676-685 ◽

Cited By ~ 44

Author(s):

Richard J. Lewis ◽

Christina I. Schroeder ◽

Jenny Ekberg ◽

Katherine J. Nielsen ◽

Marion Loughnan ◽

...

Keyword(s):

Sodium Channels ◽

Potent Inhibitor ◽

Voltage Gated ◽

Structure Activity ◽

Voltage Gated Sodium Channels

Download Full-text

Total Synthesis of 11-Saxitoxinethanoic Acid and Evaluation of its Inhibitory Activity on Voltage-Gated Sodium Channels

Angewandte Chemie ◽

10.1002/ange.201604155 ◽

2016 ◽

Vol 128 (38) ◽

pp. 11772-11775 ◽

Cited By ~ 7

Author(s):

Chao Wang ◽

Mana Oki ◽

Toru Nishikawa ◽

Daisuke Harada ◽

Mari Yotsu-Yamashita ◽

...

Keyword(s):

Total Synthesis ◽

Sodium Channels ◽

Inhibitory Activity ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

Download Full-text

Voltage-gated sodium channels and pain

e-Neuroforum ◽

10.1515/nf-2017-a017 ◽

2017 ◽

Vol 23 (3) ◽

Cited By ~ 1

Author(s):

Carla Nau ◽

Enrico Leipold

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Sodium Channels ◽

Action Potentials ◽

Afferent Pathways ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

The Central Nervous System

AbstractPainful stimuli are detected by specialized neurons, nociceptors, and are translated into action potentials, that are conducted along afferent pathways into the central nervous system, where they are conceived as pain. Voltage-gated sodium channels (Na

Download Full-text

Recording action potential propagation in single axons using multi-electrode arrays

10.1101/126425 ◽

2017 ◽

Cited By ~ 4

Author(s):

Kenneth R. Tovar ◽

Daniel C. Bridges ◽

Bian Wu ◽

Connor Randall ◽

Morgane Audouard ◽

...

Keyword(s):

Central Nervous System ◽

Action Potential ◽

Sodium Channels ◽

Action Potentials ◽

Extracellular Recording ◽

Electrode Arrays ◽

Action Potential Propagation ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Axonal Arbors

AbstractThe small caliber of central nervous system (CNS) axons makes routine study of axonal physiology relatively difficult. However, while recording extracellular action potentials from neurons cultured on planer multi-electrode arrays (MEAs) we found activity among groups of electrodes consistent with action potential propagation in single neurons. Action potential propagation was evident as widespread, repetitive cooccurrence of extracellular action potentials (eAPs) among groups of electrodes. These eAPs occurred with invariant sequences and inter-electrode latencies that were consistent with reported measures of action potential propagation in unmyelinated axons. Within co-active electrode groups, the inter-electrode eAP latencies were temperature sensitive, as expected for action potential propagation. Our data are consistent with these signals primarily reflecting axonal action potential propagation, from axons with a high density of voltage-gated sodium channels. Repeated codetection of eAPs by multiple electrodes confirmed these eAPs are from individual neurons and averaging these eAPs revealed sub-threshold events at other electrodes. The sequence of electrodes at which eAPs co-occur uniquely identifies these neurons, allowing us to monitor spiking of single identified neurons within neuronal ensembles. We recorded dynamic changes in single axon physiology such as simultaneous increases and decreases in excitability in different portions of single axonal arbors over several hours. Over several weeks, we measured changes in inter-electrode propagation latencies and ongoing changes in excitability in different regions of single axonal arbors. We recorded action potential propagation signals in human induced pluripotent stem cell-derived neurons which could thus be used to study axonal physiology in human disease models.Significance StatementStudying the physiology of central nervous system axons is limited by the technical challenges of recording from axons with pairs of patch or extracellular electrodes at two places along single axons. We studied action potential propagation in single axonal arbors with extracellular recording with multi-electrode arrays. These recordings were non-invasive and were done from several sites of small caliber axons and branches. Unlike conventional extracellular recording, we unambiguously identified and labelled the neuronal source of propagating action potentials. We manipulated and quantified action potential propagation and found a surprisingly high density of axonal voltage-gated sodium channels. Our experiments also demonstrate that the excitability of different portions of axonal arbors can be independently regulated on time scales from hours to weeks.

Download Full-text

The periodic axon membrane skeleton leads to high-density sodium nanodomains but does not impact action potentials

10.1101/2021.02.23.432468 ◽

2021 ◽

Author(s):

Zhaojie Chai ◽

Anastasios V. Tzingonunis ◽

George Lykotrafitis

Keyword(s):

Sodium Channel ◽

Sodium Channels ◽

Action Potentials ◽

High Density ◽

Homogeneous Distribution ◽

Voltage Gated ◽

Periodic Distribution ◽

Voltage Gated Sodium Channels ◽

The Impact ◽

Periodic Arrangement

ABSTRACTRecent work has established that axons have a periodic skeleton structure comprising of azimuthal actin rings connected via longitudinal spectrin tetramer filaments. This structure endows the axon with structural integrity and mechanical stability. Additionally, voltage-gated sodium channels follow the periodicity of the active-spectrin arrangement, spaced ∼190 nm segments apart. The impact of this periodic sodium channel arrangement on the generation and propagation of action potentials is unknown. To address this question, we simulated an action potential using the Hodgkin-Huxley formalism in a cylindrical compartment but instead of using a homogeneous distribution of voltage-gated sodium channels in the membrane, we applied the experimentally determined periodic arrangement. We found that the periodic distribution of voltage-gated sodium channels does not significantly affect the generation or propagation of action potentials, but instead leads to high-density sodium channel nanodomains. This work provides a foundation for future studies investigating the role of the voltage-gated sodium channel periodic arrangement in the axon.

Download Full-text