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Voltage-gated sodium channel

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https://www.readbyqxmd.com/read/28213505/revealing-the-concealed-nature-of-long-qt-type-3-syndrome
#1
Amara Greer-Short, Sharon A George, Steven Poelzing, Seth H Weinberg
BACKGROUND: Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed "self-attenuation...
February 2017: Circulation. Arrhythmia and Electrophysiology
https://www.readbyqxmd.com/read/28213447/the-drosophila-postsynaptic-deg-enac-channel-ppk29-contributes-to-excitatory-neurotransmission
#2
Alexis Hill, Xingguo Zheng, Xiling Li, Ross McKinney, Dion Dickman, Yehuda Ben-Shahar
The protein family of Degenerin/Epithelial Sodium Channels (DEG/ENaC) is comprised of diverse animal-specific, non-voltage-gated ion channels that play important roles in regulating cationic gradients across epithelial barriers. Some family members are also enriched in neural tissues in both vertebrates and invertebrates. However, the specific neurophysiological functions of most DEG/ENaC-encoding genes remain poorly understood. The fruit fly Drosophila melanogaster is an excellent model for deciphering the functions of DEG/ENaC genes because its genome encodes an exceptionally large number of DEG/ENaC subunits termed pickpocket (ppk) 1-31 Here we demonstrate that ppk29 contributes specifically to the postsynaptic modulation of excitatory synaptic transmission at the larval neuromuscular junction (NMJ)...
February 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28205593/imaging-cardiac-scn5a-using-the-novel-f-18-radiotracer-radiocaine
#3
Jacob M Hooker, Martin G Strebl, Frederick A Schroeder, Hsiao-Ying Wey, Amrut V Ambardekar, Timothy A McKinsey, Matthias Schoenberger
The key function of the heart, a well-orchestrated series of contractions, is controlled by cardiac action potentials. These action potentials are initiated and propagated by a single isoform of voltage gated sodium channels - SCN5A. However, linking changes in SCN5A expression levels to human disease in vivo has not yet been possible. Radiocaine, an F-18 radiotracer for positron emission tomography (PET), is the first SCN5A imaging agent in the heart. Explants from healthy and failing human hearts were compared using radiocaine autoradiography to determine that the failing heart has ~30% lower SCN5A levels - the first evidence of changes in SCN5A expression in humans as a function of disease...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28205548/the-complete-structure-of-an-activated-open-sodium-channel
#4
Altin Sula, Jennifer Booker, Leo C T Ng, Claire E Naylor, Paul G DeCaen, B A Wallace
Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. The cycling of Navs through open, closed and inactivated states, and their closely choreographed relationships with the activities of other ion channels lead to exquisite control of intracellular ion concentrations in both prokaryotes and eukaryotes. Here we present the 2.45 Å resolution crystal structure of the complete NavMs prokaryotic sodium channel in a fully open conformation...
February 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28202723/mapping-of-voltage-sensor-positions-in-resting-and-inactivated-mammalian-sodium-channels-by-lret
#5
Tomoya Kubota, Thomas Durek, Bobo Dang, Rocio K Finol-Urdaneta, David J Craik, Stephen B H Kent, Robert J French, Francisco Bezanilla, Ana M Correa
Voltage-gated sodium channels (Navs) play crucial roles in excitable cells. Although vertebrate Nav function has been extensively studied, the detailed structural basis for voltage-dependent gating mechanisms remain obscure. We have assessed the structural changes of the Nav voltage sensor domain using lanthanide-based resonance energy transfer (LRET) between the rat skeletal muscle voltage-gated sodium channel (Nav1.4) and fluorescently labeled Nav1.4-targeting toxins. We generated donor constructs with genetically encoded lanthanide-binding tags (LBTs) inserted at the extracellular end of the S4 segment of each domain (with a single LBT per construct)...
February 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28202576/differential-effect-of-brief-electrical-stimulation-on-voltage-gated-potassium-channels
#6
Morven Alison Cameron, Amr Al Abed, Yossi Buskila, Socrates Dokos, Nigel H Lovell, John W Morley
Electrical stimulation of neuronal tissue is a promising strategy to treat a variety of neurological disorders. The mechanism of neuronal activation by external electrical stimulation is governed by voltage-gated ion channels. This stimulus, typically brief in nature, leads to membrane potential depolarization, which increases ion flow across the membrane by increasing the open probability of these voltage-gated channels. In spiking neurons, it is activation of voltage-gated sodium channels (NaV-channels) that leads to action potential generation...
February 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28195313/neuronal-sodium-channels-emerging-components-of-the-nano-machinery-of-cardiac-calcium-cycling
#7
Rengasayee Veeraraghavan, Sándor Györke, Przemysław B Radwański
Excitation-contraction coupling (ECC) is the bridge between cardiac electrical activation and mechanical contraction. It is driven by the influx of Ca(2+) across the sarcolemma triggering Ca(2+) release from the sarcoplasmic reticulum (SR) - a process termed Ca(2+) -induced Ca(2+) release (CICR) - followed by re-sequestration of Ca(2+) into the SR. The sodium calcium exchanger (NCX) inextricably couples the cycling of Ca(2+) and Na(+) in cardiac myocytes. Thus, influx of Na(+) via voltage-gated Na(+) channels (NaV ) has emerged as an important regulator of CICR both in health and in disease...
February 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28193882/neuronal-hyperexcitability-in-a-mouse-model-of-scn8a-epileptic-encephalopathy
#8
Luis F Lopez-Santiago, Yukun Yuan, Jacy L Wagnon, Jacob M Hull, Chad R Frasier, Heather A O'Malley, Miriam H Meisler, Lori L Isom
Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel gene SCN8A Here, we investigated the neuronal phenotype of a mouse model expressing the gain-of-function SCN8A patient mutation, p.Asn1768Asp (Nav1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation...
February 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28192153/comparison-of-the-acute-inhibitory-effects-of-tetrodotoxin-ttx-in-rat-and-human-neuronal-networks-for-risk-assessment-purposes
#9
Emma E J Kasteel, Remco H S Westerink
Tetrodotoxin (TTX) is an extremely toxic marine neurotoxin. TTX inhibits voltage-gated sodium channels, resulting in a potentially lethal inhibition of neurotransmission. Despite numerous intoxications in Asia and Europe, limited (human) toxicological data are available for TTX. Additionally, the degree of interspecies differences for TTX is not well established, hampering the use of available (animal) data for human risk assessment and establishing regulatory limits for TTX concentrations in (shell)fish. We therefore used micro-electrode array (MEA) recordings as an integrated measure of neurotransmission to demonstrate that TTX inhibits neuronal electrical activity in both primary rat cortical cultures and human-induced pluripotent stem cell (hIPSC)-derived iCell(®) neurons in co-culture with hIPSC-derived iCell(®) astrocytes, with IC50 values of 7 and 10nM, respectively...
February 9, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28191886/sirtuin-1-regulates-cardiac-electrical-activity-by-deacetylating-the-cardiac-sodium-channel
#10
Ajit Vikram, Christopher M Lewarchik, Jin-Young Yoon, Asma Naqvi, Santosh Kumar, Gina M Morgan, Julia S Jacobs, Qiuxia Li, Young-Rae Kim, Modar Kassan, Jing Liu, Mohanad Gabani, Ajay Kumar, Haider Mehdi, Xiaodong Zhu, Xiaoqun Guan, William Kutschke, Xiaoming Zhang, Ryan L Boudreau, Shengchuan Dai, Daniel S Matasic, Saet-Byel Jung, Kenneth B Margulies, Vikas Kumar, Markus M Bachschmid, Barry London, Kaikobad Irani
The voltage-gated cardiac Na(+) channel (Nav1.5), encoded by the SCN5A gene, conducts the inward depolarizing cardiac Na(+) current (INa) and is vital for normal cardiac electrical activity. Inherited loss-of-function mutations in SCN5A lead to defects in the generation and conduction of the cardiac electrical impulse and are associated with various arrhythmia phenotypes. Here we show that sirtuin 1 deacetylase (Sirt1) deacetylates Nav1.5 at lysine 1479 (K1479) and stimulates INa via lysine-deacetylation-mediated trafficking of Nav1...
February 13, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28188741/molecular-dynamics-study-of-ion-transport-through-an-open-model-of-voltage-gated-sodium-channel
#11
Yang Li, Ruining Sun, Huihui Liu, Haipeng Gong
Voltage-gated sodium (NaV) channels are critical in the signal transduction of excitable cells. In this work, we modeled the open conformation for the pore domain of a prokaryotic NaV channel (NaVRh), and used molecular dynamics simulations to track the translocation of dozens of Na(+) ions through the channel in the presence of a physiological transmembrane ion concentration gradient and a transmembrane electrical field that was closer to the physiological one than previous studies. Channel conductance was then estimated from simulations on the wide-type and DEKA mutant of NaVRh...
February 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28184187/ankyrin-g-membrane-partners-drive-the-establishment-and-maintenance-of-the-axon-initial-segment
#12
Christophe Leterrier, Nadine Clerc, Fanny Rueda-Boroni, Audrey Montersino, Bénédicte Dargent, Francis Castets
The axon initial segment (AIS) is a highly specialized neuronal compartment that plays a key role in neuronal development and excitability. It concentrates multiple membrane proteins such as ion channels and cell adhesion molecules (CAMs) that are recruited to the AIS by the scaffold protein ankyrin G (ankG). The crucial function of ankG in the anchoring of AIS membrane components is well established, but a reciprocal role of membrane partners in ankG targeting and stabilization remained elusive. In rat cultured hippocampal neurons and cortical organotypic slices, we found that shRNA-mediated knockdown of ankG membrane partners (voltage-gated sodium channels (Nav) or neurofascin-186) led to a decrease of ankG concentration and perturbed the AIS formation and maintenance...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28183995/structure-of-a-eukaryotic-voltage-gated-sodium-channel-at-near-atomic-resolution
#13
Huaizong Shen, Qiang Zhou, Xiaojing Pan, Zhangqiang Li, Jianping Wu, Nieng Yan
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. They are associated with a variety of channelopathies and are targeted by multiple pharmaceutical drugs and natural toxins. Here, we report the cryo-EM structure of a putative Nav channel from American cockroach (designated NavPaS) at 3.8-Å resolution. The voltage sensing domains (VSDs) of the four repeats exhibit distinct conformations. The entrance to the asymmetric selectivity filter vestibule is guarded by heavily glycosylated and disulfide bond-stabilized extracellular loops...
February 9, 2017: Science
https://www.readbyqxmd.com/read/28182562/in-silico-modeling-of-the-functional-role-of-reduced-sialylation-in-sodium-and-potassium-channel-gating-of-mouse-ventricular-myocytes
#14
Dongping Du, Hui Yang, Andrew R Ednie, Eric S Bennett
Cardiac ion channels are highly glycosylated membrane proteins, with up to 30% of the protein's mass containing glycans. Heart diseases often accompany individuals with congenital disorders of glycosylation (CDG). However, cardiac dysfunction among CDG patients is not yet fully understood. There is an urgent need to study how aberrant glycosylation impacts cardiac electrical signaling. Our previous works reported that congenitally reduced sialylation achieved through deletion of the sialyltransferase gene, ST3Gal4, leads to altered gating of voltage-gated Na+ and K+ channels (Nav and Kv, respectively)...
February 6, 2017: IEEE Journal of Biomedical and Health Informatics
https://www.readbyqxmd.com/read/28176636/discovery-of-species-selective-and-resistance-breaking-anticholinesterase-insecticides-for-the-malaria-mosquito
#15
Paul R Carlier, Jeffrey R Bloomquist, Max Totrov, Jianyong Li
Great reductions in malaria mortality have been accomplished in the last 15 years, in part due to the widespread roll-out of insecticide-treated bednets across sub-Saharan Africa. To date, these nets only employ pyrethroids, insecticides that that target the voltage-gated sodium ion channel of the malaria vector, Anopheles gambiae. Due to the growing emergence of An. gambiae strains that are resistant to pyrethroids, there is an urgent need to develop new public health insecticides that engage a different target and possess extremely low mammalian toxicity...
February 6, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28171721/simulating-the-activation-of-voltage-sensing-domain-for-a-voltage-gated-sodium-channel-using-polarizable-force-field
#16
Rui-Ning Sun, Haipeng Gong
Voltage-gated sodium (NaV) channels play vital roles in the signal transduction of excitable cells. Upon activation of a NaV channel, the change of transmembrane voltage triggers conformational change of the voltage sensing domain, which then elicits opening of the pore domain and thus allows influx of Na+ ions. Description of this process with atomistic details is in urgent demand. In this work, we simulated the partial activation process of the voltage sensing domain of a prokaryotic NaV channel using a polarizable force field...
February 7, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28168870/annotation-of-functional-impact-of-voltage-gated-sodium-channel-mutations
#17
Valérie Hinard, Aurore Britan, Mathieu Schaeffer, Monique Zahn-Zabal, Urs Thomet, Jean-Sébastien Rougier, Amos Bairoch, Hugues Abriel, Pascale Gaudet
Voltage-gated sodium channels are pore-forming transmembrane proteins that selectively allow sodium ions to flow across the plasma membrane according to the electro-chemical gradient thus mediating the rising phase of action potentials in excitable cells and playing key roles in physiological processes such as neurotransmission, skeletal muscle contraction, heart rhythm and pain sensation. Genetic variations in the nine human genes encoding these channels are known to cause a large range of diseases affecting the nervous and cardiac systems...
February 7, 2017: Human Mutation
https://www.readbyqxmd.com/read/28166971/functional-and-molecular-characterization-of-voltage-gated-sodium-channel-nav-1-8-in-bull-spermatozoa
#18
Dharmendra Singh Chauhan, Dilip Kumar Swain, Nadeem Shah, Hanuman Prasad Yadav, Udayraj P Nakade, Vijay Kumar Singh, Rajesh Nigam, Sarvajeet Yadav, Satish Kumar Garg
The aim of our study was to characterize the voltage gated sodium channel Nav 1.8 in bull spermatozoa. Forty ejaculates were collected from four Hariana bulls and semen samples were pooled in view of the nonsignificant variations between different ejaculates. Functional characterization was undertaken using A-803467, a selective blocker of Nav1.8, and veratridine as an opener of the voltage gated sodium channels while molecular characterization was done using western blotting and indirect immunofluorescence assays...
March 1, 2017: Theriogenology
https://www.readbyqxmd.com/read/28164251/state-dependent-block-of-voltage-gated-sodium-channels-by-the-casein-kinase-1-inhibitor-ic261
#19
Karl J Föhr, Uwe Knippschild, Anna Herkommer, Michael Fauler, Christian Peifer, Michael Georgieff, Oliver Adolph
Background and Purpose IC261 (3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one) has previously been introduced as an isoform specific inhibitor of casein kinase 1 (CK1) causing cell cycle arrest or cell death of established tumor cell lines. However, it is reasonable to assume that not all antitumor activities of IC261 are mediated by the inhibition of CK1. Meanwhile there is growing evidence that functional voltage-gated sodium channels are also implicated in the progression of tumors as their blockage suppresses tumor migration and invasion of different tumor cell lines...
February 6, 2017: Investigational New Drugs
https://www.readbyqxmd.com/read/28150887/differential-effects-of-energy-deprivation-on-intracellular-sodium-homeostasis-in-neurons-and-astrocytes
#20
REVIEW
Niklas J Gerkau, Cordula Rakers, Gabor C Petzold, Christine R Rose
The maintenance of a low intracellular sodium concentration by the Na(+) /K(+) -ATPase (NKA) is critical for brain function. In both neurons and glial cells, NKA activity is required to counteract changes in the sodium gradient due to opening of voltage- and ligand-gated channels and/or activation of sodium-dependent secondary active transporters. Because NKA consumes about 50% of cellular ATP, sodium homeostasis is strictly dependent on an intact cellular energy metabolism. Despite the high energetic costs of electrical signaling, neurons do not contain significant energy stores themselves, but rely on a close metabolic interaction with surrounding astrocytes...
February 2, 2017: Journal of Neuroscience Research
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