voltage gated
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2022 ◽  
Vol 12 ◽  
Jennifer R. Deuis ◽  
Lotten Ragnarsson ◽  
Samuel D. Robinson ◽  
Zoltan Dekan ◽  
Lerena Chan ◽  

Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (NaV) channels, however relatively few venom-derived peptides with activity at the mammalian NaV1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV1.8. Eo1a is a 37-residue peptide that increases NaV1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50–20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50–15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of NaV1.1–NaV1.7, although its activity is most pronounced at NaV1.8. Investigations into the binding site of Eo1a using NaV1.7/NaV1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV1.8.

2022 ◽  
Vol 8 ◽  
Yi-Li Zheng ◽  
Xuan Su ◽  
Yu-Meng Chen ◽  
Jia-Bao Guo ◽  
Ge Song ◽  

Neuropathic pain (NP) is poorly managed, and in-depth mechanisms of gene transcriptome alterations in NP pathogenesis are not yet fully understood. To determine microRNA-related molecular mechanisms of NP and their transcriptional regulation in NP, PubMed, Embase, Web of Science and CINAHL Complete (EBSCO) were searched from inception to April 2021. Commonly dysregulated miRNAs in NP were assessed. The putative targets of these miRNAs were determined using TargetScan, Funrich, Cytoscape and String database. A total of 133 literatures containing miRNA profiles studies and experimentally verify studies were included. Venn analysis, target gene prediction analysis and functional enrichment analysis indicated several miRNAs (miR-200b-3p, miR-96, miR-182, miR-183, miR-30b, miR-155 and miR-145) and their target genes involved in known relevant pathways for NP. Targets on transient receptor potential channels, voltage-gated sodium channels and voltage-gated calcium channels may be harnessed for pain relief. A further delineation of signal processing and modulation in neuronal ensembles is key to achieving therapeutic success in future studies.

2022 ◽  
Vol 23 (2) ◽  
pp. 827
Léa Réthoré ◽  
Joohee Park ◽  
Jérôme Montnach ◽  
Sébastien Nicolas ◽  
Joseph Khoury ◽  

Thanks to the crosstalk between Na+ and Ca2+ channels, Na+ and Ca2+ homeostasis interplay in so-called excitable cells enables the generation of action potential in response to electrical stimulation. Here, we investigated the impact of persistent activation of voltage-gated Na+ (NaV) channels by neurotoxins, such as veratridine (VTD), on intracellular Ca2+ concentration ([Ca2+]i) in a model of excitable cells, the rat pituitary GH3b6 cells, in order to identify the molecular actors involved in Na+-Ca2+ homeostasis crosstalk. By combining RT-qPCR, immunoblotting, immunocytochemistry, and patch-clamp techniques, we showed that GH3b6 cells predominantly express the NaV1.3 channel subtype, which likely endorses their voltage-activated Na+ currents. Notably, these Na+ currents were blocked by ICA-121431 and activated by the β-scorpion toxin Tf2, two selective NaV1.3 channel ligands. Using Fura-2, we showed that VTD induced a [Ca2+]i increase. This effect was suppressed by the selective NaV channel blocker tetrodotoxin, as well by the selective L-type CaV channel (LTCC) blocker nifedipine. We also evidenced that crobenetine, a NaV channel blocker, abolished VTD-induced [Ca2+]i elevation, while it had no effects on LTCC. Altogether, our findings highlight a crosstalk between NaV and LTCC in GH3b6 cells, providing a new insight into the mode of action of neurotoxins.

2022 ◽  
Vol 13 (1) ◽  
Bhagyashree Kaduskar ◽  
Raja Babu Singh Kushwah ◽  
Ankush Auradkar ◽  
Annabel Guichard ◽  
Menglin Li ◽  

AbstractA recurring target-site mutation identified in various pests and disease vectors alters the voltage gated sodium channel (vgsc) gene (often referred to as knockdown resistance or kdr) to confer resistance to commonly used insecticides, pyrethroids and DDT. The ubiquity of kdr mutations poses a major global threat to the continued use of insecticides as a means for vector control. In this study, we generate common kdr mutations in isogenic laboratory Drosophila strains using CRISPR/Cas9 editing. We identify differential sensitivities to permethrin and DDT versus deltamethrin among these mutants as well as contrasting physiological consequences of two different kdr mutations. Importantly, we apply a CRISPR-based allelic-drive to replace a resistant kdr mutation with a susceptible wild-type counterpart in population cages. This successful proof-of-principle opens-up numerous possibilities including targeted reversion of insecticide-resistant populations to a native susceptible state or replacement of malaria transmitting mosquitoes with those bearing naturally occurring parasite resistant alleles.

2022 ◽  
Vol 23 (2) ◽  
pp. 784
Mingwei An ◽  
Xueling Chen ◽  
Zhuhong Yang ◽  
Jianyu Zhou ◽  
Shan Ye ◽  

The voltage-gated calcium channel (VGCC) β subunit (Cavβ) protein is a kind of cytosolic auxiliary subunit that plays an important role in regulating the surface expression and gating characteristics of high-voltage-activated (HVA) calcium channels. Ditylenchus destructor is an important plant-parasitic nematode. In the present study, the putative Cavβ subunit gene of D. destructor, namely, DdCavβ, was subjected to molecular characterization. In situ hybridization assays showed that DdCavβ was expressed in all nematode tissues. Transcriptional analyses showed that DdCavβ was expressed during each developmental stage of D. destructor, and the highest expression level was recorded in the third-stage juveniles. The crucial role of DdCavβ was verified by dsRNA soaking-mediated RNA interference (RNAi). Silencing of DdCavβ or HVA Cavα1 alone and co-silencing of the DdCavβ and HVA Cavα1 genes resulted in defective locomotion, stylet thrusting, chemotaxis, protein secretion and reproduction in D. destructor. Co-silencing of the HVA Cavα1 and Cavβ subunits showed stronger interference effects than single-gene silencing. This study provides insights for further study of VGCCs in plant-parasitic nematodes.

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 239
Sonja Langthaler ◽  
Jasmina Lozanović Šajić ◽  
Theresa Rienmüller ◽  
Seth H. Weinberg ◽  
Christian Baumgartner

The mathematical modeling of ion channel kinetics is an important tool for studying the electrophysiological mechanisms of the nerves, heart, or cancer, from a single cell to an organ. Common approaches use either a Hodgkin–Huxley (HH) or a hidden Markov model (HMM) description, depending on the level of detail of the functionality and structural changes of the underlying channel gating, and taking into account the computational effort for model simulations. Here, we introduce for the first time a novel system theory-based approach for ion channel modeling based on the concept of transfer function characterization, without a priori knowledge of the biological system, using patch clamp measurements. Using the shaker-related voltage-gated potassium channel Kv1.1 (KCNA1) as an example, we compare the established approaches, HH and HMM, with the system theory-based concept in terms of model accuracy, computational effort, the degree of electrophysiological interpretability, and methodological limitations. This highly data-driven modeling concept offers a new opportunity for the phenomenological kinetic modeling of ion channels, exhibiting exceptional accuracy and computational efficiency compared to the conventional methods. The method has a high potential to further improve the quality and computational performance of complex cell and organ model simulations, and could provide a valuable new tool in the field of next-generation in silico electrophysiology.

2022 ◽  
Lingbin Sun ◽  
Xihua Wang ◽  
Shuyuan Guan ◽  

Abstract Background Neuroinflammation plays an important role in the onset and advancement of cognitive loss and neurodegenerative disorders. The voltage-gated H channel (Hv1) has been reported to be involved in microglial activation and act as key drivers of neuroinflammation. This study aims at evaluating the mechanism of Hv1 involvement in neuroinflammation and the therapeutic potential of Hv1 inhibitor, 2-guanidinobenzimidazole (2-GBI), in a model of lipopolysaccharide (LPS)-induced neuroinflammation. Methods We investigated the influence of Hv1 inhibitor (2-GBI) on the generation of reactive oxidative species (ROS), metabolic reprogramming, and inflammatory mediators in vitro and examined the therapeutic potential of 2-GBI on microglial activation and hippocampal neuroinflammation in vivo. Novel object recognition and Y-maze were employed to assess cognitive function. Results 2-GBI reduced the LPS-induced proinflammatory response and aerobic glycolysis in microglia. HIF1α overexpression mediated aerobic glycolysis reprogramming alleviated by 2-GBI. We reported that Hv1 inhibitor exerted a protective effect on LPS-induced neuroinflammation through the ROS/HIF1α and PI3K/AKT/HIF1α pathways -mediated aerobic glycolysis. The cell death of PC12 induced by microglia-mediated neuroinflammation was reversed in a transwell co-culture system by 2-GBI. Furthermore, in vivo results suggested that 2-GBI mitigated the neuroinflammatory processes and recognition injury through regulation of microglial metabolic reprogramming. Conclusion 2-GBI protects LPS-induced neuroinflammation, neuronal cell death, and subsequently reverses the hippocampus-dependent cognitive deficits through regulation of microglial metabolic reprogramming. Taken together, these results demonstrate a key role for Hv1 in driving a pro-inflammatory microglia phenotype in neuroinflammation.

FEBS Open Bio ◽  
2022 ◽  
Gustavo Chaves ◽  
Christian Derst ◽  
Christophe Jardin ◽  
Arne Franzen ◽  
Boris Musset

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