scholarly journals Block of Voltage-Gated Sodium Channels as a Potential Novel Anti-cancer Mechanism of TIC10

2021 ◽  
Vol 12 ◽  
Author(s):  
Eva Fuchs ◽  
David Alexander Christian Messerer ◽  
Georg Karpel-Massler ◽  
Michael Fauler ◽  
Thomas Zimmer ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Sodium Channels ◽  
Tumor Therapy ◽  
Kinetic Studies ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Voltage Gated ◽  
Beneficial Effects ◽  
Voltage Gated Sodium Channels ◽  
Anti Cancer

Background: Tumor therapeutics are aimed to affect tumor cells selectively while sparing healthy ones. For this purpose, a huge variety of different drugs are in use. Recently, also blockers of voltage-gated sodium channels (VGSCs) have been recognized to possess potentially beneficial effects in tumor therapy. As these channels are a frequent target of numerous drugs, we hypothesized that currently used tumor therapeutics might have the potential to block VGSCs in addition to their classical anti-cancer activity. In the present work, we have analyzed the imipridone TIC10, which belongs to a novel class of anti-cancer compounds, for its potency to interact with VGSCs.Methods: Electrophysiological experiments were performed by means of the patch-clamp technique using heterologously expressed human heart muscle sodium channels (hNav1.5), which are among the most common subtypes of VGSCs occurring in tumor cells.Results: TIC10 angular inhibited the hNav1.5 channel in a state- but not use-dependent manner. The affinity for the resting state was weak with an extrapolated Kr of about 600 μM. TIC10 most probably did not interact with fast inactivation. In protocols for slow inactivation, a half-maximal inhibition occurred around 2 µM. This observation was confirmed by kinetic studies indicating that the interaction occurred with a slow time constant. Furthermore, TIC10 also interacted with the open channel with an affinity of approximately 4 µM. The binding site for local anesthetics or a closely related site is suggested as a possible target as the affinity for the well-characterized F1760K mutant was reduced more than 20-fold compared to wild type. Among the analyzed derivatives, ONC212 was similarly effective as TIC10 angular, while TIC10 linear more selectively interacted with the different states.Conclusion: The inhibition of VGSCs at low micromolar concentrations might add to the anti-tumor properties of TIC10.

scholarly journals Block of Voltage-Gated Sodium Channels by Atomoxetine in a State- and Use-dependent Manner

2021 ◽  
Vol 12 ◽  
Author(s):  
Karl Josef Föhr ◽  
Ariadni Nastos ◽  
Michael Fauler ◽  
Thomas Zimmer ◽  
Bettina Jungwirth ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Heart Muscle ◽  
Brain Regions ◽  
Clinical Effects ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Human Embryonic Kidney Cells ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Slow Kinetics

Atomoxetine, a neuroactive drug, is approved for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is primarily known as a high affinity blocker of the noradrenaline transporter, whereby its application leads to an increased level of the corresponding neurotransmitter in different brain regions. However, the concentrations used to obtain clinical effects are much higher than those which are required to block the transporter system. Thus, off-target effects are likely to occur. In this way, we previously identified atomoxetine as blocker of NMDA receptors. As many psychotropic drugs give rise to sudden death of cardiac origin, we now tested the hypothesis whether atomoxetine also interacts with voltage-gated sodium channels of heart muscle type in clinically relevant concentrations. Electrophysiological experiments were performed by means of the patch-clamp technique at human heart muscle sodium channels (hNav1.5) heterogeneously expressed in human embryonic kidney cells. Atomoxetine inhibited sodium channels in a state- and use-dependent manner. Atomoxetine had only a weak affinity for the resting state of the hNav1.5 (Kr: ∼ 120 µM). The efficacy of atomoxetine strongly increased with membrane depolarization, indicating that the inactivated state is an important target. A hallmark of this drug was its slow interaction. By use of different experimental settings, we concluded that the interaction occurs with the slow inactivated state as well as by slow kinetics with the fast-inactivated state. Half-maximal effective concentrations (2–3 µM) were well within the concentration range found in plasma of treated patients. Atomoxetine also interacted with the open channel. However, the interaction was not fast enough to accelerate the time constant of fast inactivation. Nevertheless, when using the inactivation-deficient hNav1.5_I408W_L409C_A410W mutant, we found that the persistent late current was blocked half maximal at about 3 µM atomoxetine. The interaction most probably occurred via the local anesthetic binding site. Atomoxetine inhibited sodium channels at a similar concentration as it is used for the treatment of ADHD. Due to its slow interaction and by inhibiting the late current, it potentially exerts antiarrhythmic properties.

scholarly journals Extremely Potent Block of Bacterial Voltage-Gated Sodium Channels by µ-Conotoxin PIIIA

Marine Drugs ◽  
2019 ◽  
Vol 17 (9) ◽  
pp. 510 ◽  
Author(s):  
Rocio K. Finol-Urdaneta ◽  
Jeffrey R. McArthur ◽  
Vyacheslav S. Korkosh ◽  
Sun Huang ◽  
Denis McMaster ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Cell Voltage ◽  
Hill Coefficient ◽  
Dependent Manner ◽  
Binding Modes ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Conducting Pathway

µ-Conotoxin PIIIA, in the sub-picomolar, range inhibits the archetypal bacterial sodium channel NaChBac (NavBh) in a voltage- and use-dependent manner. Peptide µ-conotoxins were first recognized as potent components of the venoms of fish-hunting cone snails that selectively inhibit voltage-gated skeletal muscle sodium channels, thus preventing muscle contraction. Intriguingly, computer simulations predicted that PIIIA binds to prokaryotic channel NavAb with much higher affinity than to fish (and other vertebrates) skeletal muscle sodium channel (Nav 1.4). Here, using whole-cell voltage clamp, we demonstrate that PIIIA inhibits NavBac mediated currents even more potently than predicted. From concentration-response data, with [PIIIA] varying more than 6 orders of magnitude (10−12 to 10−5 M), we estimated an IC50 = ~5 pM, maximal block of 0.95 and a Hill coefficient of 0.81 for the inhibition of peak currents. Inhibition was stronger at depolarized holding potentials and was modulated by the frequency and duration of the stimulation pulses. An important feature of the PIIIA action was acceleration of macroscopic inactivation. Docking of PIIIA in a NaChBac (NavBh) model revealed two interconvertible binding modes. In one mode, PIIIA sterically and electrostatically blocks the permeation pathway. In a second mode, apparent stabilization of the inactivated state was achieved by PIIIA binding between P2 helices and trans-membrane S5s from adjacent channel subunits, partially occluding the outer pore. Together, our experimental and computational results suggest that, besides blocking the channel-mediated currents by directly occluding the conducting pathway, PIIIA may also change the relative populations of conducting (activated) and non-conducting (inactivated) states.

scholarly journals Interleukin-6 inhibits voltage-gated sodium channel activity of cultured rat spinal cord neurons

2013 ◽  
Vol 26 (3) ◽  
pp. 170-177 ◽  
Author(s):  
Xiaoning Li ◽  
Weiqiang Chen ◽  
Jiangtao Sheng ◽  
Deliang Cao ◽  
Wanchun Wang
Keyword(s):  
Spinal Cord ◽  
Interleukin 6 ◽  
Mrna Level ◽  
Dependent Manner ◽  
Limited Information ◽  
Rat Spinal Cord ◽  
Patch Clamp Technique ◽  
Spinal Cord Neurons ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

ObjectiveInterleukin-6 (IL-6) is a pleiotropic proinflammatory cytokine that plays a key role in the injuries and diseases of the central nervous system (CNS). A voltage-gated Na+ channel (VGSC) is essential for the excitability and electrical properties of the neurons. However, there is still limited information on the role of IL-6 in voltage-gated sodium channels. Our study aimed to investigate the effects of IL-6 on Na+ currents in cultured spinal-cord neurons.MethodsVGSC currents were activated and recorded using whole-cell patch-clamp technique in the cultured rat spinal cord neurons. The effects of IL-6 concentration and exposure duration were examined. To determine whether any change in the number of channels in the plasma membrane can inhibit IL-6 on VGSC currents, we examined the expression of α1A (SCN1α) subunit mRNA level and protein level in the neurons before and after IL-6 induction using real-time polymerase chain reaction.ResultsWe verified that IL-6, through a receptor-mediated mechanism, suppressed Na+ currents in a time- and dose-dependent manner, but did not alter the voltage-dependent activation and inactivation. Gp130 was involved in this inhibition. Furthermore, the spike amplitude was also inhibited by IL-6 in the doses that decreased the Na+ currents.ConclusionVGSC currents are significantly inhibited by IL-6. Our findings reveal that the potential neuroprotection of IL-6 may result from the inhibitory effects on VGSC currents.

scholarly journals Neurosteroids Allopregnanolone Sulfate and Pregnanolone Sulfate Have Diverse Effect on the α Subunit of the Neuronal Voltage-gated Sodium Channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 Expressed in Xenopus Oocytes

2014 ◽  
Vol 121 (3) ◽  
pp. 620-631 ◽  
Author(s):  
Takafumi Horishita ◽  
Nobuyuki Yanagihara ◽  
Susumu Ueno ◽  
Yuka Sudo ◽  
Yasuhito Uezono ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Xenopus Oocytes ◽  
Sodium Current ◽  
Dependent Manner ◽  
Sodium Currents ◽  
Concentration Dependent Manner ◽  
Α Subunit ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Α Subunits

Abstract Background: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. Methods: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits. Results: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) μmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. Conclusion: APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.

A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels

2001 ◽  
Vol 85 (5) ◽  
pp. 2293-2297 ◽  
Author(s):  
Françoise Grolleau ◽  
Laurence Gamelin ◽  
Michèle Boisdron-Celle ◽  
Bruno Lapied ◽  
Marcel Pelhate ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Calcium Ions ◽  
Periplaneta Americana ◽  
Sodium Current ◽  
Current Amplitude ◽  
Patch Clamp Technique ◽  
Electrophysiological Properties ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Whole Cell Patch Clamp

Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40–500 μM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichloro-diaminocyclohexane platinum (dach-Cl2-platin) and oxalate. Oxalate (500 μM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl2-platin (500 μM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca2+ and Mg2+ is discussed.

scholarly journals Co-Application of Eugenol and QX-314 Elicits the Prolonged Blockade of Voltage-Gated Sodium Channels in Nociceptive Trigeminal Ganglion Neurons

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1513
Author(s):  
Sung-Min Hwang ◽  
Kihwan Lee ◽  
Sang-Taek Im ◽  
Eun Jin Go ◽  
Yong Ho Kim ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Trigeminal Ganglion ◽  
Transient Receptor Potential ◽  
Pain Treatment ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Noxious Heat ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Ganglion Neurons

Local anesthetics (LAs) can completely block nociception by inhibiting voltage-gated sodium channels (VGSCs), and thus, blocking action potentials (APs) within sensory neurons. As one of the several LAs, eugenol is used for dental pain treatment. It reportedly features multiple functions in regulating diverse ion channels. This study aimed to investigate the long-lasting analgesic effect of eugenol alone, as well as that of the combination of eugenol as a noxious-heat-sensitive transient receptor potential vanilloid 1 (TRPV1) channel agonist and a permanently charged sodium channel blocker (QX-314), on neuronal excitability in trigeminal ganglion (TG) neurons. Eugenol alone increased inward current in a dose-dependent manner in capsaicin-sensitive TG neurons. Eugenol also inhibited the VGSC current and AP. These effects were reversed through wash-out. The combination of eugenol and QX-314 was evaluated in the same manner. The combination completely inhibited the VGSC current and AP. However, these effects were not reversed and were continuously blocked even after wash-out. Taken together, our results suggest that, in contrast to the effect of eugenol alone, the combination of eugenol and QX-314 irreversibly and selectively blocked VGSCs in TG neurons expressing TRPV1.

scholarly journals N58A Exerts Analgesic Effect on Trigeminal Neuralgia by Regulating the MAPK Pathway and Tetrodotoxin-Resistant Sodium Channel

Toxins ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 357
Author(s):  
Chun-Li Li ◽  
Ran Yang ◽  
Yang Sun ◽  
Yuan Feng ◽  
Yong-Bo Song
Keyword(s):  
Trigeminal Neuralgia ◽  
Sodium Channels ◽  
Analgesic Effect ◽  
Mapk Pathway ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Inactivation Curve ◽  
Thermal Pain ◽  
Voltage Gated Sodium Channels ◽  
Whole Cell Patch Clamp

The primary studies have shown that scorpion analgesic peptide N58A has a significant effect on voltage-gated sodium channels (VGSCs) and plays an important role in neuropathic pain. The purpose of this study was to investigate the analgesic effect of N58A on trigeminal neuralgia (TN) and its possible mechanism. The results showed that N58A could significantly increase the threshold of mechanical pain and thermal pain and inhibit the spontaneous asymmetric scratching behavior of rats. Western blotting results showed that N58A could significantly reduce the protein phosphorylation level of ERK1/2, P38, JNK, and ERK5/CREB pathways and the expression of Nav1.8 and Nav1.9 proteins in a dose-dependent manner. The changes in current and kinetic characteristics of Nav1.8 and Nav1.9 channels in TG neurons were detected by the whole-cell patch clamp technique. The results showed that N58A significantly decreased the current density of Nav1.8 and Nav1.9 in model rats, and shifted the activation curve to hyperpolarization and the inactivation curve to depolarization. In conclusion, the analgesic effect of N58A on the chronic constriction injury of the infraorbital (IoN-CCI) model rats may be closely related to the regulation of the MAPK pathway and Nav1.8 and Nav1.9 sodium channels.

Sign in / Sign up

Export Citation Format

Share Document