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Voltage-gated sodium channel

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https://www.readbyqxmd.com/read/28534967/whole%C3%A2-exome-sequencing-identifies-a-novel-mutation-r367g-in-scn5a-to-be-associated-with-familial-cardiac-conduction-disease
#1
Rong Yu, Xue-Feng Fan, Chan Chen, Zheng-Hua Liu
Cardiac conduction disease is a primary cause of sudden cardiac death. Sodium voltage‑gated channel‑α subunit 5 (SCN5A) mutations have been reported to underlie a variety of inherited arrhythmias. Numerous disease‑causing mutations of SCN5A have been identified in patients with ≥10 different conditions, including type 3 long‑QT syndrome and Brugada syndrome. The present study investigated a family with a history of arrhythmia, with the proband having a history of arrhythmia and syncope. Whole‑exome sequencing was applied in order to detect the disease‑causing mutation in this family, and Sanger sequencing was used to confirm the co‑segregation among the family members...
May 17, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28534438/the-axonal-cytoskeleton-and-the-assembly-of-nodes-of-ranvier
#2
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
#3
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...
May 22, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28529474/mir-30b-attenuates-neuropathic-pain-by-regulating-voltage-gated-sodium-channel-nav1-3-in-rats
#4
Songxue Su, Jinping Shao, Qingzan Zhao, Xiuhua Ren, Weihua Cai, Lei Li, Qian Bai, Xuemei Chen, Bo Xu, Jian Wang, Jing Cao, Weidong Zang
Nav1.3 is a tetrodotoxin-sensitive isoform among voltage-gated sodium channels that are closely associated with neuropathic pain. It can be up-regulated following nerve injury, but its biological function remains uncertain. MicroRNAs (miRNAs) are endogenous non-coding RNAs that can regulate post-transcriptional gene expression by binding with their target mRNAs. Using Target Scan software, we discovered that SCN3A is the major target of miR-30b, and we then determined whether miR-30b regulated the expression of Nav1...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28528674/sodium-channels-and-venom-peptide-pharmacology
#5
Mathilde R Israel, Bryan Tay, Jennifer R Deuis, Irina Vetter
Venomous animals including cone snails, spiders, scorpions, anemones, and snakes have evolved a myriad of components in their venoms that target the opening and/or closing of voltage-gated sodium channels to cause devastating effects on the neuromuscular systems of predators and prey. These venom peptides, through design and serendipity, have not only contributed significantly to our understanding of sodium channel pharmacology and structure, but they also represent some of the most phyla- and isoform-selective molecules that are useful as valuable tool compounds and drug leads...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528671/voltage-gated-sodium-channel-pharmacology-insights-from-molecular-dynamics-simulations
#6
Rong Chen, Amanda Buyan, Ben Corry
Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528669/modulation-of-ion-channels-by-cysteine-rich-peptides-from-sequence-to-structure
#7
Mehdi Mobli, Eivind A B Undheim, Lachlan D Rash
Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical "toxin-to-sequence" approach to venom peptide biodiscovery...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28522439/interpreting-the-functional-role-of-a-novel-interaction-motif-in-prokaryotic-sodium-channels
#8
REVIEW
Altin Sula, B A Wallace
Voltage-gated sodium channels enable the translocation of sodium ions across cell membranes and play crucial roles in electrical signaling by initiating the action potential. In humans, mutations in sodium channels give rise to several neurological and cardiovascular diseases, and hence they are targets for pharmaceutical drug developments. Prokaryotic sodium channel crystal structures have provided detailed views of sodium channels, which by homology have suggested potentially important functionally related structural features in human sodium channels...
May 18, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28522215/blocking-voltage-gated-sodium-channels-as-a-strategy-to-suppress-pathological-cough
#9
REVIEW
Hui Sun, Marian Kollarik, Bradley J Undem
Pathological cough is thought to be secondary to inappropriate activation of vagal sensory nerves. Sensory nerves can be activated by a large number of disparate stimuli. The most relevant stimuli to block for effective anti-tussive therapy likely depend on the specific underlying pathology that is leading to the coughing. Blocking voltage-gated sodium channels (NaV) will prevent action potential initiation and conduction and therefore prevent sensory communication between the airways and brainstem. In so doing, they would be expected to inhibit evoked cough independently of the nature of the stimulus and underlying pathology...
May 15, 2017: Pulmonary Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28518218/comparison-and-optimization-of-in-silico-algorithms-for-predicting-the-pathogenicity-of-sodium-channel-variants-in-epilepsy
#10
Katherine D Holland, Thomas M Bouley, Paul S Horn
OBJECTIVE: Variants in neuronal voltage-gated sodium channel α-subunits genes SCN1A, SCN2A, and SCN8A are common in early onset epileptic encephalopathies and other autosomal dominant childhood epilepsy syndromes. However, in clinical practice, missense variants are often classified as variants of uncertain significance when missense variants are identified but heritability cannot be determined. Genetic testing reports often include results of computational tests to estimate pathogenicity and the frequency of that variant in population-based databases...
May 18, 2017: Epilepsia
https://www.readbyqxmd.com/read/28514017/isopimaric-acid-a-multi-targeting-ion-channel-modulator-reducing-excitability-and-arrhythmicity-in-a-spontaneously-beating-mouse-atrial-cell-line
#11
Sajjad Salari, Malin Silverå Ejneby, Johan Brask, Fredrik Elinder
AIM: Atrial fibrillation is the most common persistent cardiac arrhythmia, and it is not well controlled by present drugs. Because some resin acids open voltage-gated potassium channels and reduce neuronal excitability, we explored the effects of the resin acid isopimaric acid (IPA) on action potentials and ion currents in cardiomyocytes. METHODS: Spontaneously beating mouse atrial HL-1 cells were investigated with the whole-cell patch-clamp technique. RESULTS: 1-25 μmol L(-1) IPA reduced the action potential frequency by up to 50%...
May 17, 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28507035/long-term-sensitization-training-in-aplysia-decreases-the-excitability-of-a-decision-making-neuron-through-a-sodium-dependent-mechanism
#12
John S Hernandez, Marcy L Wainwright, Riccardo Mozzachiodi
In Aplysia, long-term sensitization (LTS) occurs concurrently with a suppression of feeding. At the cellular level, the suppression of feeding is accompanied by decreased excitability of decision-making neuron B51. We examined the contribution of voltage-gated Na(+) and K(+) channels to B51 decreased excitability. In a pharmacologically isolated Na(+) channels environment, LTS training significantly increased B51 firing threshold, compared with untrained controls. Conversely, in a pharmacologically isolated K(+) channels environment, no differences were observed between trained and untrained animals in either amplitude or area of B51 K(+)-dependent depolarizations...
June 2017: Learning & Memory
https://www.readbyqxmd.com/read/28503166/inhibition-of-ectopic-arginine-vasopressin-production-by-phenytoin-in-the-small-cell-lung-cancer-cell-line-lu-165
#13
Takahiro Ohta, Mitsuo Mita, Shigeru Hishinuma, Reiko Ishii-Nozawa, Kazuhisa Takahashi, Masaru Shoji
Phenytoin, a voltage-gated sodium channel (NaV channel) antagonist, reportedly inhibits arginine vasopressin (AVP) release from an isolated rat neurohypophysis. So far, it is uncertain whether phenytoin has a direct action on ectopic AVP-producing neuroendocrine tumors. We studied the effect of phenytoin on the release of copeptin, the C-terminal fragment of pro-AVP, and expression of AVP gene in the human small cell lung cancer cell line Lu-165. Cells were maintained in RPMI1640 medium with 10% fetal bovine serum and were used within the fifth passage...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28497312/phenytoin-neuroprotection-or-neurotoxicity
#14
REVIEW
Jan M Keppel Hesselink, David J Kopsky
Phenytoin is an 80-year young molecule and new indications are still emerging. The neuroprotective potential of phenytoin has been evaluated for decades. Recently, a positive phase II trial supported its further development in the treatment of optic neuritis in multiple sclerosis. In 1942, however, peripheral neuritis was first reported to be an adverse event of phenytoin, and since then a small but steady stream of publications discussed peripheral polyneuropathy as being a possible adverse event of phenytoin...
May 11, 2017: Neurological Sciences
https://www.readbyqxmd.com/read/28490751/unexpected-efficacy-of-a-novel-sodium-channel-modulator-in-dravet-syndrome
#15
Lyndsey L Anderson, Nicole A Hawkins, Christopher H Thompson, Jennifer A Kearney, Alfred L George
Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a (+/-)) mice recapitulate the severe epilepsy phenotype of Dravet syndrome and are an accepted animal model. Because clinical observations suggest conventional sodium channel blocking antiepileptic drugs may worsen the disease, we predicted the phenotype of Scn1a (+/-) mice would be exacerbated by GS967, a potent, unconventional sodium channel blocker...
May 10, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28484374/the-segregated-expression-of-voltage-gated-potassium-and-sodium-channels-in-neuronal-membranes-functional-implications-and-regulatory-mechanisms
#16
Maël Duménieu, Marie Oulé, Michael R Kreutz, Jeffrey Lopez-Rojas
Neurons are highly polarized cells with apparent functional and morphological differences between dendrites and axon. A critical determinant for the molecular and functional identity of axonal and dendritic segments is the restricted expression of voltage-gated ion channels (VGCs). Several studies show an uneven distribution of ion channels and their differential regulation within dendrites and axons, which is a prerequisite for an appropriate integration of synaptic inputs and the generation of adequate action potential (AP) firing patterns...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28475112/insect-active-toxins-with-promiscuous-pharmacology-from-the-african-theraphosid-spider-monocentropus-balfouri
#17
Jennifer J Smith, Volker Herzig, Maria P Ikonomopoulou, Sławomir Dziemborowicz, Frank Bosmans, Graham M Nicholson, Glenn F King
Many chemical insecticides are becoming less efficacious due to rising resistance in pest species, which has created much interest in the development of new, eco-friendly bioinsecticides. Since insects are the primary prey of most spiders, their venoms are a rich source of insect-active peptides that can be used as leads for new bioinsecticides or as tools to study molecular receptors that are insecticidal targets. In the present study, we isolated two insecticidal peptides, µ/ω-TRTX-Mb1a and -Mb1b, from venom of the African tarantula Monocentropus balfouri...
May 5, 2017: Toxins
https://www.readbyqxmd.com/read/28473457/pharmacologic-characterization-of-amg8379-a-potent-and-selective-small-molecule-sulfonamide-antagonist-of-the-voltage-gated-sodium-channel-nav1-7
#18
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglia (DRG) neurons with an IC50 of 3.1 nM in whole cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
May 4, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28465103/benzoxazolinone-aryl-sulfonamides-as-potent-selective-nav1-7-inhibitors-with-in-vivo-efficacy-in-a-preclinical-pain-model
#19
Joseph E Pero, Michael A Rossi, Hannah D G F Lehman, Michael J Kelly, James J Mulhearn, Scott E Wolkenberg, Matthew J Cato, Michelle K Clements, Christopher J Daley, Tracey Filzen, Eleftheria N Finger, Yun Gregan, Darrell A Henze, Aneta Jovanovska, Rebecca Klein, Richard L Kraus, Yuxing Li, Annie Liang, John M Majercak, Jacqueline Panigel, Mark O Urban, Jixin Wang, Ying-Hong Wang, Andrea K Houghton, Mark E Layton
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1...
April 22, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28464338/new-anti-seizure-arylalkyl-azole-derivatives-synthesis-in-vivo-and-in-silico-studies
#20
Suat Sari, Sevim Dalkara, Filiz Betül Kaynak, Jóhannes Reynisson, Selma Saraç, Arzu Karakurt
(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABAA Rs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure...
May 2, 2017: Archiv der Pharmazie
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