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https://www.readbyqxmd.com/read/28735751/structure-of-the-nav1-4-%C3%AE-1-complex-from-electric-eel
#1
Zhen Yan, Qiang Zhou, Lin Wang, Jianping Wu, Yanyu Zhao, Gaoxingyu Huang, Wei Peng, Huaizong Shen, Jianlin Lei, Nieng Yan
Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Here, we present the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the β1 subunit at 4.0 Å resolution. The immunoglobulin domain of β1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit "up" conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule...
July 15, 2017: Cell
https://www.readbyqxmd.com/read/28734073/differential-calcium-sensitivity-in-nav-1-5-mixed-syndrome-mutants
#2
Mena Abdelsayed, Alban-Elouen Baruteau, Karen Gibbs, Shubhayan Sanatani, Andrew D Krahn, Vincent Probst, Peter C Ruben
INTRODUCTION: Inherited arrhythmias may arise from mutations in the SCN5a gene, which encodes the cardiac voltage-gated sodium channel, NaV 1.5. Mutants in NaV 1.5 result in Brugada Syndrome (BrS1), Long-QT Syndrome (LQT3), or mixed syndromes (an overlap of BrS1/LQT3). Exercise is a potential arrhythmogenic trigger in mixed syndromes. We sought to determine the effects of elevated cytosolic calcium, common during exercise, in mixed syndrome NaV 1.5 mutants. METHODS: We used whole-cell patch-clamp to assess the biophysical properties of NaV 1...
July 22, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28734032/characterization-of-the-axon-initial-segment-of-mice-substantia-nigra-dopaminergic-neurons
#3
Cristian González-Cabrera, Rodrigo Meza, Lorena Ulloa, Paulina Merino-Sepúlveda, Valentina Luco, Ana Sanhueza, Alejandro Oñate-Ponce, J Paul Bolam, Pablo Henny
The axon initial segment (AIS) is the site of initiation of action potentials and also influences action potential waveform, firing pattern and rate. In view of the fundamental aspects of motor function and behavior that depend on the firing of substantia nigra pars compacta (SNc) dopaminergic neurons, we identified and characterized their AIS in the mouse. Immunostaining for tyrosine hydroxylase (TH), sodium channels (Nav ) and ankyrin-G (Ank-G) was used to visualize the AIS of dopaminergic neurons. Reconstructions of sampled AIS of dopaminergic neurons revealed variable lengths (12 - 60 μm) and diameters (0...
July 22, 2017: Journal of Comparative Neurology
https://www.readbyqxmd.com/read/28726749/ladder-shaped-ion-channel-ligands-current-state-of-knowledge
#4
REVIEW
Yuri B Shmukler, Denis A Nikishin
Ciguatoxins (CTX) and brevetoxins (BTX) are polycyclic ethereal compounds biosynthesized by the worldwide distributed planktonic and epibenthic dinoflagellates of Gambierdiscus and Karenia genera, correspondingly. Ciguatera, evoked by CTXs, is a type of ichthyosarcotoxism, which involves a variety of gastrointestinal and neurological symptoms, while BTXs cause so-called neurotoxic shellfish poisoning. Both types of toxins are reviewed together because of similar mechanisms of their action. These are the only molecules known to activate voltage-sensitive Na⁺-channels in mammals through a specific interaction with site 5 of its α-subunit and may compete for it, which results in an increase in neuronal excitability, neurotransmitter release and impairment of synaptic vesicle recycling...
July 20, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28720591/using-fluorescence-to-understand-%C3%AE-subunit-nav-channel-interactions
#5
Rene Barro-Soria, Sara I Liin, H Peter Larsson
No abstract text is available yet for this article.
July 18, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28720590/mechanisms-of-noncovalent-%C3%AE-subunit-regulation-of-nav-channel-gating
#6
Wandi Zhu, Taylor L Voelker, Zoltan Varga, Angela R Schubert, Jeanne M Nerbonne, Jonathan R Silva
Voltage-gated Na(+) (NaV) channels comprise a macromolecular complex whose components tailor channel function. Key components are the non-covalently bound β1 and β3 subunits that regulate channel gating, expression, and pharmacology. Here, we probe the molecular basis of this regulation by applying voltage clamp fluorometry to measure how the β subunits affect the conformational dynamics of the cardiac NaV channel (NaV1.5) voltage-sensing domains (VSDs). The pore-forming NaV1.5 α subunit contains four domains (DI-DIV), each with a VSD...
July 18, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28712915/comparative-analyses-and-implications-for-antivenom-serotherapy-of-four-moroccan-scorpion-buthus-occitanus-venoms-subspecies-tunetanus-paris-malhommei-and-mardochei
#7
Bruna Luiza Emerich, Maria Elena De Lima, Marie-France Martin-Eauclaire, Pierre E Bougis
Temporary passive immunity such as serotherapy against venoms requires the full knowledge of all venom's components. Here, four venoms from Moroccan common yellow scorpions belonging to Buthus occitanus, subspecies tunetanus, paris, malhommei, and mardochei, all collected in four different restricted areas, were analysed in deep. They were fractionated by reversed-phase high-performance liquid chromatography (RP-HPLC) and their molecular masse profile determined by off-line MALDI-TOF mass spectrometry. Characterisation of their main components was achieved by enzyme-linked immunosorbent assay (ELISA) using specific antisera against the major lethal scorpion toxins identified so far, i...
July 13, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28658526/reverse-pharmacogenomics-carbamazepine-normalizes-activation-and-attenuates-thermal-induced-hyperexcitability-of-sensory-neurons-due-to-nav1-7-mutation-i234t
#8
Yang Yang, Talia Adi, Philip Effraim, Lubin Chen, Sulayman D Dib-Hajj, Stephen G Waxman
BACKGROUND AND PURPOSE: Pharmacotherapy for pain currently involves trial-and-error. A previous study on inherited erythromelalgia (a genetic model of neuropathic pain due to mutations in voltage-gated sodium channel Nav1.7) used genomics, structural modeling, biophysical and pharmacological analyses to guide pharmacotherapy, and showed that carbamazepine normalizes voltage-dependence of activation of the Nav1.7-S241T mutant channel, reducing pain in patients carrying this mutation. However, whether this approach is applicable to other Nav mutations is still unknown...
June 28, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28635024/a-small-molecule-activator-of-nav-1-1-channels-increases-fast-spiking-interneuron-excitability-and-gabaergic-transmission-in-vitro-and-has-anti-convulsive-effects-in-vivo
#9
Kristen Frederiksen, Lu Dunguo, Jinhui Yang, Henrik Sindal Jensen, Jesper Frank Bastlund, Peter Hjørringgaard Larsen, Liu Henry, Kim Dekermendjian, Lassina Badolo, Morten Laursen, Charlotte Hougaard, Charles Yang, Niels Svenstrup, Morten Grunnet
Nav 1.1 (SCN1A) channels primarily located in gamma-aminobutyric acid (GABA)ergic fast-spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast-spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Nav 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav 1...
June 21, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28620187/discovery-and-identification-of-o-o-diethyl-o-4-5-phenyl-4-5-dihydroisoxazol-3-yl-phenyl-phosphorothioate-xp-1408-as-a-novel-mode-of-action-of-organophosphorus-insecticides
#10
Zhigang Zeng, Ying Yan, Bingfeng Wang, Niu Liu, Hanhong Xu
Organophosphorus (OP) insecticides play an important role in pest control. Many OP insecticides have been removed from the market because of their high toxicity to humans. We designed and synthesized a new OP insecticide with the goal of providing a low cost, and less toxic insecticide. The mode of action of O, O-diethyl O-(4-(5-phenyl-4, 5-dihydroisoxazol-3-yl) phenyl) phosphorothioate (XP-1408) was studied in Drosophila melanogaster. Bioassays showed that XP-1408 at a concentration of 50 mg/L delayed larval development...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607094/pharmacology-of-the-nav1-1-domain-iv-voltage-sensor-reveals-coupling-between-inactivation-gating-processes
#11
Jeremiah D Osteen, Kevin Sampson, Vivek Iyer, David Julius, Frank Bosmans
The Nav1.1 voltage-gated sodium channel is a critical contributor to excitability in the brain, where pathological loss of function leads to such disorders as epilepsy, Alzheimer's disease, and autism. This voltage-gated sodium (Nav) channel subtype also plays an important role in mechanical pain signaling by primary afferent somatosensory neurons. Therefore, pharmacologic modulation of Nav1.1 represents a potential strategy for treating excitability disorders of the brain and periphery. Inactivation is a complex aspect of Nav channel gating and consists of fast and slow components, each of which may involve a contribution from one or more voltage-sensing domains...
June 27, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28597987/trafficking-and-localization-to-the-plasma-membrane-of-nav-1-5-promoted-by-the-%C3%AE-2-subunit-is-defective-due-to-a-%C3%AE-2-mutation-associated-with-brugada-syndrome
#12
Gemma Dulsat, Sonia Palomeras, Eric Cortada, Helena Riuró, Ramon Brugada, Marcel Vergés
BACKGROUND INFORMATION: Cardiac channelopathies arise by mutations in genes encoding ion channel subunits. One example is Brugada Syndrome (BrS), which causes arrhythmias and sudden death. BrS is often associated with mutations in SCN5A, encoding Nav 1.5, the α subunit of the major cardiac voltage-gated sodium channel. This channel forms a protein complex including one or two associated β subunits as well as other proteins. RESULTS: We analyzed regulation of Nav 1...
June 9, 2017: Biology of the Cell
https://www.readbyqxmd.com/read/28591687/mtor-mediated-na-ca-2-exchange-affects-cell-proliferation-and-metastasis-of-melanoma-cells
#13
Yi Yang, Zhanpeng Luo, Yonghong Hao, Wei Ba, Rui Wang, Wenjuan Wang, Xiangyu Ding, Chengxin Li
Melanoma is a common malignant tumor, which is associated with high mortality rate. The multiple-drug resistance of tumor cells often results in failure of chemotherapy. The aim of our study is to investigate the expression of Nav 1.6 in human melanoma cells and human epidermal melanocytes. Additionally, the effect of Na+channels on Ca+ current and mTOR activity in melanoma cells were also analyzed. The protein expression levels of Nav1.6 in human melanocyte PIG1, WM266 and WM115 cells were investigated by western blot...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28560448/multiple-nav1-5-isoforms-are-functionally-expressed-in-the-brain-and-present-distinct-expression-patterns-compared-with-cardiac-nav1-5
#14
Jun Wang, Shao-Wu Ou, Yun-Fei Bai, Yun-Jie Wang, Zhi-Qing David Xu, Guo-Ming Luan
It has previously been demonstrated that there are various voltage gated sodium channel (Nav) 1.5 splice variants expressed in brain tissue. A total of nine Nav1.5 isoforms have been identified, however, the potential presence of further Nav1.5 variants expressed in brain neurons remains to be elucidated. The present study systematically investigated the expression of various Nav1.5 splice variants and their associated electrophysiological properties in the rat brain tissue, via biochemical analyses and whole‑cell patch clamp recording...
July 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28557626/response-characteristics-and-retinal-origin-of-the-photopic-negative-response-of-the-electroretinogram-in-dogs
#15
Shunsuke Takada, Junzo Kinoshita, Noriaki Iwata, Masako Imaoka, Yoshiro Tani
PURPOSE: To investigate the response characteristics and retinal origin of the photopic negative response (PhNR) of the electroretinograms (ERGs) in dogs. METHODS: Photopic ERGs were elicited by white flash stimuli of different intensities under a steady white background illumination in four anesthetized dogs. These ERGs were also recorded in the same manner after intravitreal injection of tetrodotoxin (TTX). Additionally, retinal localization of voltage-gated sodium channel Nav 1...
May 30, 2017: Current Eye Research
https://www.readbyqxmd.com/read/28557294/a-mechanism-for-nav-1-5-downregulation-and-sodium-current-decrease-in-heart-failure
#16
EDITORIAL
Sara Pagans, Marcel Vergés
The pore-forming α-subunit of the cardiac voltage-gated sodium channel, NaV 1.5, is responsible for the initial upstroke of the cardiac action potential. NaV 1.5 cell surface expression and function are modulated by its interaction with regulatory proteins and by posttranslational modifications, such as phosphorylation, arginine methylation or ubiquitination (1) . Genetic mutations in the SCN5A gene, which encodes NaV 1.5, have been associated with a variety of inherited cardiac arrhythmias, including long QT syndrome type 3, Brugada syndrome, atrial fibrillation, and congenital sick sinus syndrome...
May 30, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28542706/modulatory-features-of-the-novel-spider-toxin-%C3%AE-trtx-df1a-isolated-from-the-venom-of-the-spider-davus-fasciatus
#17
Fernanda C Cardoso, Zoltan Dekan, Jennifer J Smith, Jennifer R Deuis, Irina Vetter, Volker Herzig, Paul F Alewood, Glenn F King, Richard J Lewis
BACKGROUND AND PURPOSE: Naturally occurring dysfunction of voltage-gated sodium (NaV ) channels results in complex disorders such as chronic pain, making these channels an attractive target for new therapies. In the pursuit of novel NaV modulators, we investigated spider venoms for new inhibitors of NaV channels. EXPERIMENTAL APPROACH: We used high-throughput screens to identify a NaV modulator in venom of the spider Davus fasciatus. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modelling and a rodent pain model...
August 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28534438/the-axonal-cytoskeleton-and-the-assembly-of-nodes-of-ranvier
#18
Aniket Ghosh, Diane L Sherman, Peter J Brophy
Vertebrate nervous systems rely on rapid nerve impulse transmission to support their complex functions. Fast conduction depends on ensheathment of nerve axons by myelin-forming glia and the clustering of high concentrations of voltage-gated sodium channels (Nav) in the axonal gaps between myelinated segments. These gaps are the nodes of Ranvier. Depolarization of the axonal membrane initiates the action potential responsible for impulse transmission, and the Nav help ensure that this is restricted to nodes...
May 1, 2017: Neuroscientist: a Review Journal Bringing Neurobiology, Neurology and Psychiatry
https://www.readbyqxmd.com/read/28530638/sodium-channel-nav1-9-mutations-associated-with-insensitivity-to-pain-dampen-neuronal-excitability
#19
Jianying Huang, Carlos G Vanoye, Alison Cutts, Y Paul Goldberg, Sulayman D Dib-Hajj, Charles J Cohen, Stephen G Waxman, Alfred L George
Voltage-gated sodium channel (NaV) mutations cause genetic pain disorders that range from severe paroxysmal pain to a congenital inability to sense pain. Previous studies on NaV1.7 and NaV1.8 established clear relationships between perturbations in channel function and divergent clinical phenotypes. By contrast, studies of NaV1.9 mutations have not revealed a clear relationship of channel dysfunction with the associated and contrasting clinical phenotypes. Here, we have elucidated the functional consequences of a NaV1...
June 30, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28522250/ppargamma-agonists-rescue-increased-phosphorylation-of-fgf14-at-s226-in-the-tg2576-mouse-model-of-alzheimer-s-disease
#20
Wei-Chun J Hsu, Norelle C Wildburger, Sigmund J Haidacher, Miroslav N Nenov, Oluwarotimi Folorunso, Aditya K Singh, Brent C Chesson, Whitney F Franklin, Ibdanelo Cortez, Rovshan G Sadygov, Kelly T Dineley, Jay S Rudra, Giulio Taglialatela, Cheryl F Lichti, Larry Denner, Fernanda Laezza
BACKGROUND: Cognitive impairment in humans with Alzheimer's disease (AD) and in animal models of Aβ-pathology can be ameliorated by treatments with the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARγ) agonists, such as rosiglitazone (RSG). Previously, we demonstrated that in the Tg2576 animal model of AD, RSG treatment rescued cognitive deficits and reduced aberrant activity of granule neurons in the dentate gyrus (DG), an area critical for memory formation...
May 15, 2017: Experimental Neurology
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