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https://www.readbyqxmd.com/read/29071509/toxins-that-affect-voltage-gated-sodium-channels
#1
Yonghua Ji
Voltage-gated sodium channels (VGSCs) are critical in generation and conduction of electrical signals in multiple excitable tissues. Natural toxins, produced by animal, plant, and microorganisms, target VGSCs through diverse strategies developed over millions of years of evolutions. Studying of the diverse interaction between VGSC and VGSC-targeting toxins has been contributing to the increasing understanding of molecular structure and function, pharmacology, and drug development potential of VGSCs. This chapter aims to summarize some of the current views on the VGSC-toxin interaction based on the established receptor sites of VGSC for natural toxins...
October 26, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29071507/posttranslational-modification-of-sodium-channels
#2
Zifan Pei, Yanling Pan, Theodore R Cummins
Voltage-gated sodium channels (VGSCs) are critical determinants of excitability. The properties of VGSCs are thought to be tightly controlled. However, VGSCs are also subjected to extensive modifications. Multiple posttranslational modifications that covalently modify VGSCs in neurons and muscle have been identified. These include, but are not limited to, phosphorylation, ubiquitination, palmitoylation, nitrosylation, glycosylation, and SUMOylation. Posttranslational modifications of VGSCs can have profound impact on cellular excitability, contributing to normal and abnormal physiology...
October 26, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/29045055/c2-modified-sparteine-derivatives-are-a-new-class-of-potentially-long-acting-na-channel-blockers
#3
Vaibhavkumar S Gawali, Svilen Simeonov, Martina Drescher, Thomas Knott, Olaf Scheel, John Kudolo, Ulla Hochenegg, Alexander Roller, Hannes Todt, Nuno Maulide
The lupin alkaloid Sparteine is a well-known chiral diamine with a range of applications in asymmetric synthesis, as well as a blocker of voltage-gated Na channels (VGSCs). However, there is only scarce information on the VGSC-blocking activity of Sparteine derivatives where the structure of the parent alkaloid is retained. Herein, building on the recent renewed availability of Sparteine and derivatives we report how modification of Sparteine in position 2 produces irreversible blockers of VGSCs. These compounds could be clinically envisaged as long-lasting local anesthetics...
October 17, 2017: ChemMedChem
https://www.readbyqxmd.com/read/29017613/a-multiplex%C3%A2-pcr-for-detection-of-knockdown-resistance-mutations-v1016g-and-f1534c-in-pyrethroid-resistant-aedes-aegypti
#4
Jassada Saingamsook, Atiporn Saeung, Jintana Yanola, Nongkran Lumjuan, Catherine Walton, Pradya Somboon
BACKGROUND: Mutation of the voltage-gated sodium channel (VGSC) gene, or knockdown resistance (kdr) gene, is an important resistance mechanism of the dengue vector Aedes aegypti mosquitoes against pyrethroids. In many countries in Asia, a valine to glycine substitution (V1016G) and a phenylalanine to cysteine substitution (F1534C) are common in Ae. aegypti populations. The G1016 and C1534 allele frequencies have been increasing in recent years, and hence there is a need to have a simple and inexpensive tool to monitor the alleles in large scale...
October 10, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28972985/local-selection-in-the-presence-of-high-levels-of-gene-flow-evidence-of-heterogeneous-insecticide-selection-pressure-across-ugandan-culex-quinquefasciatus-populations
#5
Walter Fabricio Silva Martins, Craig Stephen Wilding, Keith Steen, Henry Mawejje, Tiago Rodrigues Antão, Martin James Donnelly
BACKGROUND: Culex quinquefasciatus collected in Uganda, where no vector control interventions directly targeting this species have been conducted, was used as a model to determine if it is possible to detect heterogeneities in selection pressure driven by insecticide application targeting other insect species. METHODOLOGY/PRINCIPAL FINDINGS: Population genetic structure was assessed through microsatellite analysis, and the impact of insecticide pressure by genotyping two target-site mutations, Vgsc-1014F of the voltage-gated sodium channel target of pyrethroid and DDT insecticides, and Ace1-119S of the acetylcholinesterase gene, target of carbamate and organophosphate insecticides...
October 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28939974/sodium-channel-trafficking
#6
A Mercier, P Bois, A Chatelier
Voltage-gated sodium channels (VGSC) are critical determinants of cellular electrical activity through the control of initiation and propagation of action potential. To ensure this role, these proteins are not consistently delivered to the plasma membrane but undergo drastic quality controls throughout various adaptive processes such as biosynthesis, anterograde and retrograde trafficking, and membrane targeting. In pathological conditions, this quality control could lead to the retention of functional VGSC and is therefore the target of different pharmacological approaches...
September 23, 2017: Handbook of Experimental Pharmacology
https://www.readbyqxmd.com/read/28927993/voltage-gated-sodium-channel-%C3%AE-subunits-the-power-outside-the-pore-in-brain-development-and-disease
#7
REVIEW
Jacob M Hull, Lori L Isom
Voltage gated sodium channels (VGSCs) were first identified in terms of their role in the upstroke of the action potential. The underlying proteins were later identified as saxitoxin and scorpion toxin receptors consisting of α and β subunits. We now know that VGSCs are heterotrimeric complexes consisting of a single pore forming α subunit joined by two β subunits; a noncovalently linked β1 or β3 and a covalently linked β2 or β4 subunit. VGSC α subunits contain all the machinery necessary for channel cell surface expression, ion conduction, voltage sensing, gating, and inactivation, in one central, polytopic, transmembrane protein...
September 18, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28874684/damage-free-peripheral-nerve-stimulation-by-12-ns-pulsed-electric-field
#8
Maura Casciola, Shu Xiao, Andrei G Pakhomov
Modern technologies enable deep tissue focusing of nanosecond pulsed electric field (nsPEF) for non-invasive nerve and muscle stimulation. However, it is not known if PEF orders of magnitude shorter than the activation time of voltage-gated sodium channels (VGSC) would evoke action potentials (APs). One plausible scenario requires the loss of membrane integrity (electroporation) and resulting depolarization as an intermediate step. We report, for the first time, that the excitation of a peripheral nerve can be accomplished by 12-ns PEF without electroporation...
September 5, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28867800/ciguatoxins-evoke-potent-cgrp-release-by-activation-of-voltage-gated-sodium-channel-subtypes-nav1-9-nav1-7-and-nav1-1
#9
Filip Touska, Simon Sattler, Philipp Malsch, Richard J Lewis, Peter W Reeh, Katharina Zimmermann
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals...
August 30, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28865490/mapping-insecticide-resistance-and-characterization-of-resistance-mechanisms-in-anopheles-arabiensis-diptera-culicidae-in-ethiopia
#10
Eba Alemayehu, Abebe Asale, Kasahun Eba, Kefelegn Getahun, Kora Tushune, Astrid Bryon, Evangelia Morou, John Vontas, Thomas Van Leeuwen, Luc Duchateau, Delenasaw Yewhalaw
BACKGROUND: The emergence and spread of insecticide resistance in the major African malaria vectors Anopheles gambiae (s.s.) and An. arabiensis may compromise the current vector control interventions and threatens the global malaria control and elimination efforts. METHODS: Insecticide resistance was monitored in several study sites in Ethiopia from 2013 to 2015 using papers impregnated with discriminating concentrations of DDT, deltamethrin, bendiocarb, propoxur, malathion, fenitrothion and pirimiphos-methyl, following the WHO insecticide susceptibility test procedure...
September 2, 2017: Parasites & Vectors
https://www.readbyqxmd.com/read/28863150/a-single-markov-type-kinetic-model-accounting-for-the-macroscopic-currents-of-all-human-voltage-gated-sodium-channel-isoforms
#11
Pietro Balbi, Paolo Massobrio, Jeanette Hellgren Kotaleski
Modelling ionic channels represents a fundamental step towards developing biologically detailed neuron models. Until recently, the voltage-gated ion channels have been mainly modelled according to the formalism introduced by the seminal works of Hodgkin and Huxley (HH). However, following the continuing achievements in the biophysical and molecular comprehension of these pore-forming transmembrane proteins, the HH formalism turned out to carry limitations and inconsistencies in reproducing the ion-channels electrophysiological behaviour...
September 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28831242/modeling-the-human-nav1-5-sodium-channel-structural-and-mechanistic-insights-of-ion-permeation-and-drug-blockade
#12
Marawan Ahmed, Horia Jalily Hasani, Aravindhan Ganesan, Michael Houghton, Khaled Barakat
Abnormalities in the human Nav1.5 (hNav1.5) voltage-gated sodium ion channel (VGSC) are associated with a wide range of cardiac problems and diseases in humans. Current structural models of hNav1.5 are still far from complete and, consequently, their ability to study atomistic interactions of this channel is very limited. Here, we report a comprehensive atomistic model of the hNav1.5 ion channel, constructed using homology modeling technique and refined through long molecular dynamics simulations (680 ns) in the lipid membrane bilayer...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28793859/investigating-knockdown-resistance-kdr-mechanism-against-pyrethroids-ddt-in-the-malaria-vector-anopheles-funestus-across-africa
#13
Helen Irving, Charles S Wondji
BACKGROUND: Understanding the molecular basis of insecticide resistance is key to improve the surveillance and monitoring of malaria vector populations under control. In the major malaria vector Anopheles funestus, little is currently known about the role of the knockdown resistance (kdr) mechanism. Here, we investigated the presence and contribution of knockdown resistance (kdr) to pyrethroids/DDT resistance observed in Anopheles funestus across Africa. RESULTS: Pyrosequencing genotyping and sequencing of the voltage gated sodium channel (VGSC) gene did not detect the common L1014F mutation in field collected An...
August 9, 2017: BMC Genetics
https://www.readbyqxmd.com/read/28782435/rufinamide-pretreatment-attenuates-ischemia-reperfusion-injury-in-the-gerbil-hippocampus
#14
Chan Woo Park, Tae-Kyeong Lee, Jeong Hwi Cho, In Hye Kim, Jae-Chul Lee, Bich-Na Shin, Ji Hyeon Ahn, Sung Koo Kim, Myoung Cheol Shin, Taek Geun Ohk, Jun Hwi Cho, Moo-Ho Won, Young Joo Lee, Jeong Yeol Seo, Joon Ha Park
OBJECTIVES: Rufinamide, a voltage-gated sodium channel (VGSC) blocker, is widely used for the clinical treatment of seizures associated with Lennox-Gastaut syndrome. Previous studies have demonstrated that VGSC blockers have neuroprotective properties against ischemic damage following experimental cerebral ischemia. However, protective effects of rufinamide against cerebral ischemic insults have not been addressed. Therefore, in the present study, we firstly examined neuroprotective effects of rufinamide using a gerbil model of transient global cerebral ischemia...
August 7, 2017: Neurological Research
https://www.readbyqxmd.com/read/28734106/insecticide-resistance-in-trialeurodes-vaporariorum-populations-and-novel-diagnostics-for-kdr-mutations
#15
Despoina Evr Kapantaidaki, Eldem Sadikoglou, Dimitra Tsakireli, Vasileios Kampanis, Marianna Stavrakaki, Corinna Schorn, Aris Ilias, Maria Riga, George Tsiamis, Ralf Nauen, George Skavdis, John Vontas, Anastasia Tsagkarakou
BACKGROUND: Neonicotinoids, pyrethroids and ketoenols, are currently used for the control of Trialeurodes vaporariorum (Hemiptera: Aleyrodidae). In this study, insecticide resistance status and mechanisms were investigated by classical bioassays and molecular techniques. RESULTS: Dose response bioassays were performed on 19 Greek populations, among the 35 different whitefly populations used for the whole analysis. Resistance factors scaled up to 207-, 4657- and 59- fold, for imidacloprid, bifenthrin and spiromesifen, respectively...
July 22, 2017: Pest Management Science
https://www.readbyqxmd.com/read/28725028/detection-and-quantitation-of-copy-number-variation-in-the-voltage-gated-sodium-channel-gene-of-the-mosquito-culex-quinquefasciatus
#16
Walter Fabricio Silva Martins, Krishanthi Subramaniam, Keith Steen, Henry Mawejje, Triantafillos Liloglou, Martin James Donnelly, Craig Stephen Wilding
Insecticide resistance is typically associated with alterations to the insecticidal target-site or with gene expression variation at loci involved in insecticide detoxification. In some species copy number variation (CNV) of target site loci (e.g. the Ace-1 target site of carbamate insecticides) or detoxification genes has been implicated in the resistance phenotype. We show that field-collected Ugandan Culex quinquefasciatus display CNV for the voltage-gated sodium channel gene (Vgsc), target-site of pyrethroid and organochlorine insecticides...
July 19, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28698102/neonatal-nav1-5-protein-expression-in-normal-adult-human-tissues-and-breast-cancer
#17
Rezan Fahrioglu Yamaci, Scott P Fraser, Esra Battaloglu, Handan Kaya, Kamil Erguler, Christopher S Foster, Mustafa B A Djamgoz
Expression of the neonatal splice variant of the voltage-gated sodium channel α-subunit (VGSC) subtype Nav1.5 (nNav1.5), encoded by the gene SCN5A, was shown earlier to be upregulated in human breast cancer (BCa), both in vitro and in vivo. Channel activity promoted BCa invasion of Matrigel(®)in vitro and metastasis in vivo. Consequently, expression of nNav1.5 has been proposed as a functional biomarker of BCa cells with metastatic potential. Here, we have determined immunohistochemically both nNav1.5 and total VGSC (tVGSC) protein expression in a range of adult human tissues...
August 2017: Pathology, Research and Practice
https://www.readbyqxmd.com/read/28679467/effects-of-a-novel-sodium-channel-blocker-gsk2339345-in-patients-with-refractory-chronic-cough%C3%A2
#18
RANDOMIZED CONTROLLED TRIAL
Jaclyn A Smith, Lorcan P A McGarvey, Huda Badri, Imran Satia, Francis Warren, Sarah Siederer, Lia Liefaard, Robert D Murdoch, Kathryn Povey, Joanna Marks-Konczalik
OBJECTIVE: Voltage-gated sodium channels (VGSC) are important in the initiation and propagation of action potentials in afferent sensory nerve fibers responsible for evoking cough. This study investigated the efficacy of GSK2339345, a VGSC inhibitor, in the treatment of refractory chronic cough (RCC). METHODS: A three-part randomized, double-blind, placebo-controlled, cross-over study was conducted in the UK. In part A, patients with RCC received two inhaled doses of either GSK2339345 or placebo, 4 hours apart during three study periods...
September 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28655765/parallel-homodimer-structures-of-the-extracellular-domains-of-the-voltage-gated-sodium-channel-%C3%AE-4-subunit-explain-its-role-in-cell-cell-adhesion
#19
Hideaki Shimizu, Asako Tosaki, Noboru Ohsawa, Yoshiko Ishizuka-Katsura, Shisako Shoji, Haruko Miyazaki, Fumitaka Oyama, Takaho Terada, Mikako Shirouzu, Shun-Ichi Sekine, Nobuyuki Nukina, Shigeyuki Yokoyama
Voltage-gated sodium channels (VGSCs) are transmembrane proteins required for the generation of action potentials in excitable cells and essential for propagating electrical impulses along nerve cells. VGSCs are complexes of a pore-forming α subunit and auxiliary β subunits, designated as β1/β1B-β4 (encoded by SCN1B-4B, respectively), which also function in cell-cell adhesion. We previously reported the structural basis for the trans homophilic interaction of the β4 subunit, which contributes to its adhesive function...
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28608751/molecular-modelling-studies-of-kdr-mutations-in-voltage-gated-sodium-channel-revealed-significant-conformational-variations-contributing-to-insecticide-resistance
#20
Nanda Kumar Yellapu, Jeyakodi Gopal, Gunasekaran Kasinahtan, Jambulingam Purushothaman
Voltage gated sodium channels (VGSC) of mosquito vectors are the primary targets of DDT and other synthetic pyrethroids used in public health programs. The knockdown resistant (kdr) mutations in VGSC are associated with the insecticide resistance especially in Anophelines. The present study is aimed to emphasize and demarcate the impact of three kdr-mutations such as L1014S, L1014F and L1014H on insecticide resistance. The membrane model of sodium transport domain of VGSC (STD-VGSC) was constructed using de novo approach based on domain and trans-membrane predictions...
June 13, 2017: Journal of Biomolecular Structure & Dynamics
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