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Voltage-gated sodium channel

Bernd R Gardill, Ricardo E Rivera-Acevedo, Ching-Chieh Tung, Mark Okon, Lawrence P McIntosh, Filip Van Petegem
Voltage-gated sodium channels (NaV ) are responsible for the rapid depolarization of many excitable cells. They readily inactivate, a process where currents diminish after milliseconds of channel opening. They are also targets for a multitude of disease-causing mutations, many of which have been shown to affect inactivation. A cluster of disease mutations, linked to Long-QT and Brugada syndromes, is located in a C-terminal EF-hand like domain of NaV 1.5, the predominant cardiac sodium channel isoform. Previous studies have suggested interactions with the III-IV linker, a cytosolic element directly involved in inactivation...
March 14, 2018: Scientific Reports
Thomas Berk, Stephen D Silberstein
BACKGROUND: Lidocaine, an amide anesthetic, has been used in the treatment of a wide variety of pain disorders for over 75 years. In addition to pain control, lidocaine is an anti-arrhythmic agent and has anti-inflammatory properties. Lidocaine's unique properties, including nonlinear pharmacokinetics, have limited its modern-day use. OBJECTIVE: The purpose of this review is to offer a better understanding of the properties of this unique treatment, which we hope will allow more practitioners to offer this to their patients...
March 14, 2018: Headache
Michael L Yuan, Ian J Wang
Spatial heterogeneity in the strength or agents of selection can lead to geographic variation in ecologically important phenotypes. Many dendrobatid frogs sequester alkaloid toxins from their diets and often exhibit fixed mutations at NaV1.4, a voltage-gated sodium ion channel associated with alkaloid toxin resistance. Yet previous studies have noted an absence of resistance mutations in individuals from several species known to sequester alkaloid toxins, suggesting possible intraspecific variation for alkaloid resistance in these species...
2018: PloS One
Jian Payandeh, David H Hackos
The voltage-gated sodium (Nav) channel Nav1.7 has been the focus of intense investigation in recent years. Human genetics studies of individuals with gain-of-function and loss-of-function mutations in the Nav1.7 channel have implicated Nav1.7 as playing a critical role in pain. Therefore, selective inhibition of Nav1.7 represents a potentially new analgesic strategy that is expected to be devoid of the significant liabilities associated with available treatment options. Although the identification and development of selective Nav channel modulators have historically been challenging, a number of recent publications has demonstrated progression of increasingly subtype-selective small molecules and peptides toward potential use in preclinical or clinical studies...
March 13, 2018: Handbook of Experimental Pharmacology
Peng Yu, Lili Hu, Jinyan Xie, Sisi Chen, Lin Huang, Zixuan Xu, Xiao Liu, Qiongqiong Zhou, Ping Yuan, Xia Yan, Jiejin Jin, Yang Shen, Wengen Zhu, Linghua Fu, Qi Chen, Jianhua Yu, Jianxin Hu, Qing Cao, Rong Wan, Kui Hong
BACKGROUND: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias...
February 27, 2018: International Journal of Cardiology
Martin Loynaz Prieto, Kamyar Firouzi, Butrus T Khuri-Yakub, Merritt Maduke
Ultrasound (US) can modulate the electrical activity of the excitable tissues, but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here, we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV 1...
March 7, 2018: Ultrasound in Medicine & Biology
Eugen Brailoiu, Christine L Barlow, Servio H Ramirez, Mary E Abood, G Cristina Brailoiu
Platelet-activating factor (PAF) is a potent phospholipid mediator that exerts various pathophysiological effects by interacting with a G protein-coupled receptor. PAF has been reported to increase the permeability of the blood-brain barrier (BBB) via incompletely characterized mechanisms. We investigated the effect of PAF on rat brain microvascular endothelial cells (RBMVEC), a critical component of the BBB. PAF produced a dose-dependent increase in cytosolic Ca2+ concentration; the effect was prevented by the PAF receptor antagonist, WEB2086...
March 6, 2018: Neuroscience
Csaba Fekete, Csaba Vastagh, Ádám Dénes, Erik Hrabovszky, Gábor Nyiri, Imre Kalló, Zsolt Liposits, Miklós Sárvári
Microglia are instrumental for recognition and elimination of amyloid β1-42 oligomers (AβO), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AβO infusion evoked a sustained inflammatory response including activation of NF-κB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors...
March 6, 2018: Neuroscience
Silvia Corrochano, Gonzalo Blanco, Debbie Williams, Jessica Wettstein, Michelle Simon, Saumya Kumar, Lee Moir, Thomas Agnew, Michelle Stewart, Allison Landman, Vassilios N Kotiadis, Michael R Duchen, Henning Wackerhage, David C Rubinsztein, Steve D M Brown, Abraham Acevedo-Arozena
Polyglutamine expansions in the huntingtin gene cause Huntington's disease (HD). Huntingtin is ubiquitously expressed, leading to pathological alterations also in peripheral organs. Variations in the length of the polyglutamine tract explain up to 70% of the age-at-onset variance, with the rest of the variance attributed to genetic and environmental modifiers. To identify novel disease modifiers, we performed an unbiased mutagenesis screen on an HD mouse model, identifying a mutation in the skeletal muscle voltage-gated sodium channel (Scn4a, termed 'draggen' mutation) as a novel disease enhancer...
March 2, 2018: Human Molecular Genetics
Marit Poffers, Nathalie Bühne, Christine Herzog, Anja Thorenz, Rongjun Chen, Faikah Güler, Axel Hage, Andreas Leffler, Frank Echtermeyer
BACKGROUND: Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. METHODS: Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury...
March 6, 2018: Anesthesiology
Dongfang Tang, Zhen Xiao, Yan Xu, Jiao Zeng, Dezheng Peng, Songping Liang, Cheng Tang, Zhonghua Liu
Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaV s). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaV s in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaV s to the hyperpolarized direction...
February 28, 2018: Peptides
Lubin Chen, Jianying Huang, Peng Zhao, Anna-Karin Persson, Fadia B Dib-Hajj, Xiaoyang Cheng, Andrew Tan, Stephen G Waxman, Sulayman D Dib-Hajj
Voltage-gated sodium channels NaV 1.7, NaV 1.8 and NaV 1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV 1.6 in pain is less understood. In this study, we selectively knocked out NaV 1.6 in dorsal root ganglion (DRG) neurons, using NaV 1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV 1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain...
March 1, 2018: Scientific Reports
Kunsala T D S Yapa, Jennifer Deuis, Amelia A Peters, Paraic A Kenny, Sarah J Roberts-Thomson, Irina Vetter, Gregory R Monteith
AIMS: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. MATERIALS AND METHODS: Cell viability and migration of breast cancer cells was determined using MTS assays and wound healing assays, respectively. RNA-Seq analysis of breast tumours and qPCR in breast cancer cell lines were used to assess mRNA levels of ion channels...
February 26, 2018: Life Sciences
A Alcántara Montero, C I Sánchez Carnerero
Once patients have failed first line therapy, there is an apparent lack of knowledge on how to proceed with choosing subsequent therapy. To choose amongst alternative agents, an understanding of pharmacology, pharmacokinetics, and available evidence in targeting various pain conditions is necessary. This article focuses on the use of the carboxamide class of voltage-gated sodium channel blockers (carbamazepine, oxcarbazepine, eslicarbazepine acetate) for adjunct pain medication management; including research updates in pharmacology, pharmacokinetics, and evidence for pain along on this therapeutic group with promising future areas of research...
February 26, 2018: Revista Española de Anestesiología y Reanimación
Mena Abdelsayed, Manpreet Ruprai, Peter C Ruben
E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa ) passed by the cardiac voltage-gated sodium channel (NaV 1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa . In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium...
February 26, 2018: Scientific Reports
Vera Geraldes, Sérgio Laranjo, Isabel Rocha
Hypertension is a prevalent and major health problem, involving a complex integration of different organ systems, including the central nervous system (CNS). The CNS and the hypothalamus in particular are intricately involved in the pathogenesis of hypertension. In fact, evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive and increased blood pressure. Several mechanisms have been proposed to contribute to hypothalamic-driven sympathetic activity, including altered ion channel function...
February 26, 2018: Current Hypertension Reports
Roland Eric Yessinou, Yao Akpo, Aboubakar Sidick, Camus Adoligbe, Issaka Youssao Abdou Karim, Martin Akogbeto, Souaïbou Farougou
Ticks are obligate haematophagous arthropods, causing heavy losses in affected livestock. The objective of this study is to investigate phenotypic and genotypic resistance in Rhipicephalus microplus populations from Benin. Engorged female adult ticks were collected from cattle in two districts of Benin. Bioassays, biochemical and molecular tests were carried out on these ticks to determine the phenotypic, enzymatic and genetic status of resistance. Results of bioassays showed high resistance factors (RF > 41)...
February 16, 2018: Ticks and Tick-borne Diseases
Ilya Pozdnyakov, Olga Matantseva, Sergei Skarlato
Four-domain voltage-gated cation channels (FVCCs) represent a large family of pseudo-tetrameric ion channels which includes voltage-gated calcium (Cav ) and sodium (Nav ) channels, as well as their homologues. These transmembrane proteins are involved in a wide range of physiological processes, such as membrane excitability, rhythmical activity, intracellular signalling, etc. Information about actual diversity and phylogenetic relationships of FVCCs across the eukaryotic tree of life is scarce. We for the first time performed a taxonomically broad phylogenetic analysis of 277 FVCC sequences from a variety of eukaryotes and showed that many groups of eukaryotic organisms have their own clades of FVCCs...
February 23, 2018: Scientific Reports
Tânia C Gonçalves, Rachid Boukaiba, Jordi Molgó, Muriel Amar, Michel Partiseti, Denis Servent, Evelyne Benoit
The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV 1.7 subtype of voltage-gated sodium (NaV ) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV 1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms...
February 20, 2018: Neuropharmacology
Mónica Rubio Ayala, Tatiana Syrovets, Susanne Hafner, Vitalii Zablotskii, Alexandr Dejneka, Thomas Simmet
Cellular function is modulated by the electric membrane potential controlling intracellular physiology and signal propagation from a motor neuron to a muscle fiber resulting in muscle contraction. Unlike electric fields, magnetic fields are not attenuated by biological materials and penetrate deep into the tissue. We used complex spatiotemporal magnetic fields (17-70 mT) to control intracellular signaling in skeletal muscle cells. By changing different parameters of the alternating magnetic field (amplitude, inversion time, rotation frequency), we induced transient depolarization of cellular membranes leading to i) Na+ influx through voltage-gated sodium channels (VGSC), ii) cytosolic calcium increase, and iii) VGSC- and ryanodine receptor-dependent increase of actin polymerization...
February 16, 2018: Biomaterials
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