Voltage-Gated Sodium Channels Mediating Conduction in Vagal Motor Fibers Innervating the Esophageal Striated Muscle

The vagal motor fibers innervating the esophageal striated muscle are essential for esophageal motility including swallowing and vomiting. However, it is unknown which subtypes of voltage-gated sodium channels (NaV1s) regulate action potential conduction in these efferent nerve fibers. The information on the NaV1s subtypes is necessary for understanding their potential side effects on upper gut, as novel inhibitors of NaV1s are developed for treatment of pain. We used isolated superfused (35 °C) vagally-innervated mouse esophagus striated muscle preparation (mucosa removed) to measure isometric contractions of circular striated muscle evoked by electrical stimulation of the vagus nerve. NaV1 inhibitors were applied to the de-sheathed segment of the vagus nerve. Tetrodotoxin (TTX) applied to the vagus nerve completely abolished electrically evoked contractions. The selective NaV1.7 inhibitor PF-05089771 alone partially inhibited contractions and caused a >3-fold rightward shift in the TTX concentration-inhibition curve. The NaV1.1, NaV1.2 and NaV1.3 group inhibitor ICA-121431 failed to inhibit contractions, or to alter TTX concentration-inhibition curves in the absence or in the presence of PF-05089771. RT-PCR indicated lack of NaV1.4 expression in nucleus ambiguus and dorsal motor nucleus of the vagus nerve, which contain motor and preganglionic neurons projecting to the esophagus. We conclude that the action potential conduction in the vagal motor fibers to the esophageal striated muscle in the mouse is mediated by TTX-sensitive voltage gated sodium channels including NaV1.7 and most probably NaV1.6. The role of NaV1.6 is supported by ruling out other TTX-sensitive NaV1s (NaV1.1-1.4) in the NaV1.7-independent conduction.

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Voltage-gated sodium channels in neocortical pyramidal neurons display Cole-Moore activation kinetics

10.1101/164210 ◽

2017 ◽

Author(s):

Mara Almog ◽

Tal Barkai ◽

Angelika Lampert ◽

Alon Korngreen

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Pyramidal Neurons ◽

Brain Slices ◽

Action Potential Generation ◽

Potential Generation ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Gating Mechanism ◽

Cortical Pyramidal Neurons

AbstractExploring the properties of action potentials is a crucial step towards a better understanding of the computational properties of single neurons and neural networks. The voltage-gated sodium channel is a key player in action potential generation. A comprehensive grasp of the gating mechanism of this channel can shed light on the biophysics of action potential generation. Most models of voltage-gated sodium channels assume it obeys a concerted Hodgkin and Huxley kinetic gating scheme. Here we performed high resolution voltage-clamp experiments from nucleated patches extracted from the soma of layer 5 (L5) cortical pyramidal neurons in rat brain slices. We show that the gating mechanism does not follow traditional Hodgkin and Huxley kinetics and that much of the channel voltage-dependence is probably due to rapid closed-closed transitions that lead to substantial onset latency reminiscent of the Cole-Moore effect observed in voltage-gated potassium conductances. This may have key implications for the role of sodium channels in synaptic integration and action potential generation.

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Effect of Oxaliplatin on Voltage-Gated Sodium Channels in Peripheral Neuropathic Pain

Processes ◽

10.3390/pr8060680 ◽

2020 ◽

Vol 8 (6) ◽

pp. 680 ◽

Cited By ~ 2

Author(s):

Woojin Kim

Keyword(s):

Neuropathic Pain ◽

Action Potential ◽

Sodium Channels ◽

Sodium Current ◽

Voltage Response ◽

Treatment Schedule ◽

Voltage Gated ◽

Peripheral Neurons ◽

Voltage Gated Sodium Channels ◽

Current Voltage

Oxaliplatin is a chemotherapeutic drug widely used to treat various types of tumors. However, it can induce a serious peripheral neuropathy characterized by cold and mechanical allodynia that can even disrupt the treatment schedule. Since the approval of the agent, many laboratories, including ours, have focused their research on finding a drug or method to decrease this side effect. However, to date no drug that can effectively reduce the pain without causing any adverse events has been developed, and the mechanism of the action of oxaliplatin is not clearly understood. On the dorsal root ganglia (DRG) sensory neurons, oxaliplatin is reported to modify their functions, such as the propagation of the action potential and induction of neuropathic pain. Voltage-gated sodium channels in the DRG neurons are important, as they play a major role in the excitability of the cell by initiating the action potential. Thus, in this small review, eight studies that investigated the effect of oxaliplatin on sodium channels of peripheral neurons have been included. Its effects on the duration of the action potential, peak of the sodium current, voltage–response relationship, inactivation current, and sensitivity to tetrodotoxin (TTX) are discussed.

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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.

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Action potential changes associated with a slowed inactivation of cardiac voltage-gated sodium channels by KB130015

British Journal of Pharmacology ◽

10.1038/sj.bjp.0705379 ◽

2003 ◽

Vol 139 (8) ◽

pp. 1469-1479 ◽

Cited By ~ 13

Author(s):

R Macianskiene ◽

V Bito ◽

L Raeymaekers ◽

B Brandts ◽

K R Sipido ◽

...

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Voltage Gated ◽

Voltage Gated Sodium Channels

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Voltage gating of ion channels

Quarterly Reviews of Biophysics ◽

10.1017/s0033583500002894 ◽

1994 ◽

Vol 27 (1) ◽

pp. 1-40 ◽

Cited By ~ 283

Author(s):

F. J. Sigworth

Keyword(s):

Ion Channels ◽

Action Potential ◽

Sodium Channels ◽

Calcium Ions ◽

Neurotransmitter Release ◽

Voltage Gating ◽

Voltage Gated ◽

Voltage Gated Calcium Channels ◽

Voltage Gated Sodium Channels ◽

Voltage Gated Ion Channels

Voltage-gated ion channels are membrane proteins that play a central role in the propagation and transduction of cellular signals (Hille, 1992). Calcium ions entering cells through voltage-gated calcium channels serve as the trigger for neurotransmitter release, muscle contraction, and the release of hormones. Voltage-gated sodium channels initiate the nerve action potential and provide for its rapid propagation because the ion fluxes through these channels regeneratively cause more channels to open.

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Sensory renal innervation: a kidney-specific firing activity due to a unique expression pattern of voltage-gated sodium channels?

AJP Renal Physiology ◽

10.1152/ajprenal.00011.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F491-F497 ◽

Cited By ~ 7

Author(s):

Wolfgang Freisinger ◽

Johannes Schatz ◽

Tilmann Ditting ◽

Angelika Lampert ◽

Sonja Heinlein ◽

...

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Sensory Neurons ◽

Firing Pattern ◽

Drg Neurons ◽

Action Potential Firing ◽

Tonic Firing ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Potential Firing

Sensory neurons with afferent axons from the kidney are extraordinary in their response to electrical stimulation. More than 50% exhibit a tonic firing pattern, i.e., sustained action potential firing throughout depolarizing, pointing to an increased excitability, whereas nonrenal neurons show mainly a phasic response, i.e., less than five action potentials. Here we investigated whether these peculiar firing characteristics of renal afferent neurons are due to differences in the expression of voltage-gated sodium channels (Navs). Dorsal root ganglion (DRG) neurons from rats (Th11-L2) were recorded by the current-clamp technique and distinguished as “tonic” or “phasic.” In voltage-clamp recordings, Navs were characterized by their tetrodotoxoxin (TTX) sensitivity, and their molecular identity was revealed by RT-PCR. The firing pattern of 66 DRG neurons (41 renal and 25 nonrenal) was investigated. Renal neurons exhibited more often a tonic firing pattern (56.1 vs. 12%). Tonic neurons showed a more positive threshold (−21.75 ± 1.43 vs.−29.33 ± 1.63 mV; P < 0.05), a higher overshoot (56.74 [53.6–60.96] vs. 46.79 mV [38.63–54.75]; P < 0.05) and longer action potential duration (4.61 [4.15–5.85] vs. 3.35 ms [2.12–5.67]; P < 0.05). These findings point to an increased presence of the TTX-resistant Navs 1.8 and 1.9. Furthermore, tonic neurons exhibited a relatively higher portion of TTX-resistant sodium currents. Interestingly, mRNA expression of TTX-resistant sodium channels was significantly increased in renal, predominantly tonic, DRG neurons. Hence, under physiological conditions, renal sensory neurons exhibit predominantly a firing pattern associated with higher excitability. Our findings support that this is due to an increased expression and activation of TTX-resistant Navs.

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A Progress on the Application of Tetrodotoxin

E3S Web of Conferences ◽

10.1051/e3sconf/202129203065 ◽

2021 ◽

Vol 292 ◽

pp. 03065

Author(s):

Zhaojia Wang ◽

Zhenning Zhou

Keyword(s):

Neuropathic Pain ◽

Action Potential ◽

Cancer Pain ◽

Sodium Channels ◽

The Body ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

New Generation ◽

Different Parts

Tetrodotoxin (TTX), a blocker of sodium channels, exists in the pufferfish, amphibians, and octopus, and originated in endosymbiont-vibrio. Researches have confirmed that TTX affected the action potential through the regulation of voltage-gated sodium channels (VGSCs) and the ingestion of TTX inhibits the nerve signal’s transmission, showing symptoms like rapid weakening and paralysis of the muscles. Recent research shows that TTX’s medical value as the analgesic is mainly focused. The comparison on efficacy among placebo, TTX, and opioids manifests that TTX is healthy and effective in treating neuropathic pain. Moreover, since the drug is synthesized by TTX, it can block specific neurons to alleviate the pain on different parts of the body accurately. Currently speaking, TTX has been widely used as medicine for the alleviation of cancer pain. The mechanism, symptoms, application, and treatment are thoroughly discussed to popularize TTX and pass the “torch” to the new generation because there is still a long way to go—the unsolved mysteries of TTX awaiting humans.

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Carisbamate, a novel neuromodulator, inhibits voltage-gated sodium channels and action potential firing of rat hippocampal neurons

Epilepsy Research ◽

10.1016/j.eplepsyres.2008.09.006 ◽

2009 ◽

Vol 83 (1) ◽

pp. 66-72 ◽

Cited By ~ 23

Author(s):

Yi Liu ◽

George J. Yohrling ◽

Yan Wang ◽

Tasha L. Hutchinson ◽

Douglas E. Brenneman ◽

...

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Hippocampal Neurons ◽

Action Potential Firing ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Potential Firing

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Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00122.2019 ◽

2020 ◽

Vol 319 (4) ◽

pp. G443-G453

Author(s):

Fei Ru ◽

Nikoleta Pavelkova ◽

Jeffrey L. Krajewski ◽

Jeff S. McDermott ◽

Bradley J. Undem ◽

...

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Stimulus Intensity ◽

Nerve Terminals ◽

Voltage Gated ◽

Low Intensity ◽

C Fibers ◽

Voltage Gated Sodium Channels ◽

Action Potential Initiation ◽

Potential Initiation

We report that pharmacologically distinguishable voltage-gated sodium channels (NaV1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on NaV1.7; however, additional tetrodotoxin (TTX)-sensitive NaV1s are recruited at higher intensity of distention. This is the first demonstration that NaV1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.

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Contribution of tetrodotoxin-sensitive voltage-gated sodium channels (NaV1) to action potential discharge from mouse esophageal tension mechanoreceptors

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00199.2021 ◽

2021 ◽

Author(s):

Stephen Hadley ◽

Mayur J Patil ◽

Nikoleta Pavelkova ◽

Marian Kollarik ◽

Thomas E Taylor-Clark

Keyword(s):

Action Potential ◽

Sodium Channels ◽

Esophageal Motility ◽

Critical Role ◽

Inhibitory Effect ◽

Sensory Afferents ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Almost All ◽

Electrical Signaling

Action potentials depend on voltage-gated sodium channels (NaV1s), which have nine alpha subtypes. NaV1 inhibition is a target for pathologies involving excitable cells such as pain. However, because NaV1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific NaV1s and their inhibition in mouse esophageal mechanoreceptors - non-nociceptive vagal sensory afferents that are stimulated by low threshold mechanical distension, which regulate esophageal motility. Using single fiber electrophysiology, we found mechanoreceptor responses to esophageal distension were abolished by tetrodotoxin. Single cell RT-PCR revealed that esophageal-labeled TRPV1-negative vagal neurons expressed multiple tetrodotoxin-sensitive NaV1s: NaV1.7 (almost all neurons) and NaV1.1, NaV1.2 and NaV1.6 (in ~50% of neurons). Inhibition of NaV1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of NaV1.1 and NaV1.6, using ICA-121341, had a similar small inhibitory effect. The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. Inhibition of NaV1.2, NaV1.6 and NaV1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus all four tetrodotoxin-sensitive NaV1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those NaV1s necessary for vagal action potential conduction, as demonstrated using GCaMP6s imaging of esophageal vagal neurons during electrical stimulation. Tetrodotoxin-sensitive conduction was abolished in many esophageal neurons by PF-05089771 alone, indicating a critical role of NaV1.7. In summary, multiple NaV1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus inhibition of individual NaV1s would likely have minimal effect on afferent regulation of esophageal motility.

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