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https://www.readbyqxmd.com/read/29773519/the-neurosteroid-allopregnanolone-sulfate-inhibits-na-v-1-3-%C3%AE-subunit-containing-voltage-gated-sodium-channels-expressed-in-xenopus-oocytes
#1
Takafumi Horishita, Nobuyuki Yanagihara, Susumu Ueno, Dan Okura, Reiko Horishita, Tomoko Minami, Yuichi Ogata, Yuka Sudo, Yasuhito Uezono, Takashi Kawasaki
The neurosteroid allopregnanolone has potent analgesic effects, and its potential use for neuropathic pain is supported by recent reports. However, the analgesic mechanisms are obscure. The voltage-gated sodium channels (Nav ) α subunit Nav 1.3 is thought to play an essential role in neuropathic pain. Here, we report the effects of allopregnanolone sulfate (APAS) on sodium currents (INa ) in Xenopus oocytes expressing Nav 1.3 with β1 or β3 subunits. APAS suppressed INa of Nav 1.3 with β1 and β3 in a concentration-dependent manner (IC50 values; 75 and 26 μmol/L)...
March 30, 2018: Journal of Pharmacological Sciences
https://www.readbyqxmd.com/read/29770866/meucin-49-a-multifunctional-scorpion-venom-peptide-with-bactericidal-synergy-with-neurotoxins
#2
Bin Gao, Julie Dalziel, Simone Tanzi, Shunyi Zhu
Besides key roles in prey capture and predator defense, scorpion venom also functions as internal immune agents protecting the venom gland from infection and external immune agents cleaning saprophytic microbes from their own body surfaces. However, antimicrobials (typically antimicrobial peptides, AMPs) in the venom often exist in low abundance that might exclude their immune role alone, leaving an open question with regard to their in vivo biological function. Here, we report the bactericidal activity of seven peptides isolated from the scorpion Mesobuthus eupeus venom, including one classical α-helical AMP and five ion channel-targeted neurotoxins...
May 16, 2018: Amino Acids
https://www.readbyqxmd.com/read/29769724/structural-basis-for-gating-pore-current-in-periodic-paralysis
#3
Daohua Jiang, Tamer M Gamal El-Din, Christopher Ing, Peilong Lu, Régis Pomès, Ning Zheng, William A Catterall
Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases characterized by episodes of flaccid muscle weakness1,2 . They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav 1.4 or the calcium channel Cav 1.11,2 . Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis1,2 by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state3,4 ...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29760657/purkinje-cell-signaling-deficits-in-animal-models-of-ataxia
#4
REVIEW
Eriola Hoxha, Ilaria Balbo, Maria Concetta Miniaci, Filippo Tempia
Purkinje cell (PC) dysfunction or degeneration is the most frequent finding in animal models with ataxic symptoms. Mutations affecting intrinsic membrane properties can lead to ataxia by altering the firing rate of PCs or their firing pattern. However, the relationship between specific firing alterations and motor symptoms is not yet clear, and in some cases PC dysfunction precedes the onset of ataxic signs. Moreover, a great variety of ionic and synaptic mechanisms can affect PC signaling, resulting in different features of motor dysfunction...
2018: Frontiers in Synaptic Neuroscience
https://www.readbyqxmd.com/read/29744740/co-expression-of-%C3%AE-subunits-with-the-voltage-gated-sodium-channel-na-v-1-7-the-importance-of-subunit-association-and-phosphorylation-and-their-effects-on-channel-pharmacology-and-biophysics
#5
Maxim V Sokolov, Petra Henrich-Noack, Carina Raynoschek, Bo Franzén, Olof Larsson, Martin Main, Michael Dabrowski
The voltage-gated sodium ion channel NaV 1.7 is crucial in pain signaling. We examined how auxiliary β2 and β3 subunits and the phosphorylation state of the channel influence its biophysical properties and pharmacology. The human NaV 1.7α subunit was co-expressed with either β2 or β3 subunits in HEK-293 cells. The β2 subunits and the NaV 1.7α, however, were barely associated as evidenced by immunoprecipitation. Therefore, the β2 subunits did not change the biophysical properties of the channel. In contrast, β3 subunit was clearly associated with NaV 1...
May 10, 2018: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/29740331/voltage-gated-sodium-channel-%C3%AE-1-%C3%AE-1b-subunits-regulate-cardiac-physiology-and-pathophysiology
#6
REVIEW
Nnamdi Edokobi, Lori L Isom
Cardiac myocyte contraction is initiated by a set of intricately orchestrated electrical impulses, collectively known as action potentials (APs). Voltage-gated sodium channels (NaV s) are responsible for the upstroke and propagation of APs in excitable cells, including cardiomyocytes. NaV s consist of a single, pore-forming α subunit and two different β subunits. The β subunits are multifunctional cell adhesion molecules and channel modulators that have cell type and subcellular domain specific functional effects...
2018: Frontiers in Physiology
https://www.readbyqxmd.com/read/29739425/naked-mole-rat-cortical-neurons-are-resistant-to-acid-induced-cell-death
#7
Zoé Husson, Ewan St John Smith
Regulation of brain pH is a critical homeostatic process and changes in brain pH modulate various ion channels and receptors and thus neuronal excitability. Tissue acidosis, resulting from hypoxia or hypercapnia, can activate various proteins and ion channels, among which acid-sensing ion channels (ASICs) a family of primarily Na+ permeable ion channels, which alongside classical excitotoxicity causes neuronal death. Naked mole-rats (NMRs, Heterocephalus glaber) are long-lived, fossorial, eusocial rodents that display remarkable behavioral/cellular hypoxia and hypercapnia resistance...
May 9, 2018: Molecular Brain
https://www.readbyqxmd.com/read/29735899/determination-of-the-%C3%AE-conotoxin-piiia-specificity-against-voltage-gated-sodium-channels-from-binding-energy-calculations
#8
Fangling Chen, Wenxin Huang, Tao Jiang, Rilei Yu
Voltage-gated sodium (NaV ) channels generate and propagate action potentials in excitable cells, and several NaV subtypes have become important targets for pain management. The μ-conotoxins inhibit subtypes of the NaV with varied specificity but often lack of specificity to interested subtypes. Engineering the selectivity of the μ-conotoxins presents considerable complexity and challenge, as it involves the optimization of their binding affinities to multiple highly conserved NaV subtypes. In this study, a model of NaV 1...
May 7, 2018: Marine Drugs
https://www.readbyqxmd.com/read/29734505/identification-of-phosphorylation-sites-and-binding-pockets-for-modulation-of-na-v-1-5-channel-by-fyn-tyrosine-kinase
#9
Shahid Muhammad Iqbal, Mohammed Aufy, Waheed Shabbir, Rosa Lemmens-Gruber
Cardiac sodium channel NaV 1.5 is the predominant form of sodium channels in cardiomyocytes, which exists as a macromolecular complex and interacts with multiple protein partners. Fyn kinase is one of the interacting proteins which co-localize, phosphorylate and modulate the NaV 1.5 channel. To elaborate this interaction we created expression vectors for the N-terminal, intracellular loop and C-terminal regions of the NaV 1.5 channel, to express in HEK-293 cells. By co-immunoprecipitation and anti-phosphotyrosine blotting, we identified proline-rich binding sites for Fyn kinase in the N-terminal, IC-loopi-ii and C-terminal...
May 7, 2018: FEBS Journal
https://www.readbyqxmd.com/read/29728980/backbone-resonance-assignments-of-complexes-of-apo-human-calmodulin-bound-to-iq-motif-peptides-of-voltage-dependent-sodium-channels-na-v-1-1-na-v-1-4-and-na-v-1-7
#10
Holly M Isbell, Adina M Kilpatrick, Zesen Lin, Ryan Mahling, Madeline A Shea
Human voltage-gated sodium (NaV ) channels are critical for initiating and propagating action potentials in excitable cells. Nine isoforms have different roles but similar topologies, with a pore-forming α-subunit and auxiliary transmembrane β-subunits. NaV pathologies lead to debilitating conditions including epilepsy, chronic pain, cardiac arrhythmias, and skeletal muscle paralysis. The ubiquitous calcium sensor calmodulin (CaM) binds to an IQ motif in the C-terminal tail of the α-subunit of all NaV isoforms, and contributes to calcium-dependent pore-gating in some channels...
May 4, 2018: Biomolecular NMR Assignments
https://www.readbyqxmd.com/read/29728395/-scn5a-na-v-1-5-variant-functional-perturbation-and-clinical-presentation-variants-of-a-certain-significance
#11
Brett M Kroncke, Andrew M Glazer, Derek K Smith, Jeffrey D Blume, Dan M Roden
BACKGROUND: Accurately predicting the impact of rare nonsynonymous variants on disease risk is an important goal in precision medicine. Variants in the cardiac sodium channel SCN5A (protein NaV 1.5; voltage-dependent cardiac Na+ channel) are associated with multiple arrhythmia disorders, including Brugada syndrome and long QT syndrome. Rare SCN5A variants also occur in ≈1% of unaffected individuals. We hypothesized that in vitro electrophysiological functional parameters explain a statistically significant portion of the variability in disease penetrance...
May 2018: Circulation. Genomic and precision medicine
https://www.readbyqxmd.com/read/29726066/partial-loss-of-function-of-sodium-channel-scn8a-in-familial-isolated-myoclonus
#12
Jacy L Wagnon, Niccolò E Mencacci, Bryan S Barker, Eric R Wenger, Kailash P Bhatia, Bettina Balint, Miryam Carecchio, Nicholas W Wood, Manoj K Patel, Miriam H Meisler
Variants in the neuronal sodium channel gene SCN8A have been implicated in several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter the biophysical properties of the channel. Complete loss-of-function variants of SCN8A have been identified in cases of isolated intellectual disability. We now report a novel heterozygous SCN8A variant, p.Pro1719Arg in a small pedigree with five family members affected with autosomal dominant upper limb isolated myoclonus without seizures or cognitive impairment...
May 3, 2018: Human Mutation
https://www.readbyqxmd.com/read/29723257/pharmacological-characterization-of-potent-and-selective-nav1-7-inhibitors-engineered-from-chilobrachys-jingzhao-tarantula-venom-peptide-jztx-v
#13
Bryan D Moyer, Justin K Murray, Joseph Ligutti, Kristin Andrews, Philippe Favreau, John B Jordan, Josie H Lee, Dong Liu, Jason Long, Kelvin Sham, Licheng Shi, Reto Stöcklin, Bin Wu, Ruoyuan Yin, Violeta Yu, Anruo Zou, Kaustav Biswas, Les P Miranda
Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1...
2018: PloS One
https://www.readbyqxmd.com/read/29719455/preemptive-application-of-qx-314-attenuates-trigeminal-neuropathic-mechanical-allodynia-in-rats
#14
Jeong-Ho Yoon, Jo-Young Son, Min-Ji Kim, Song-Hee Kang, Jin-Sook Ju, Yong-Chul Bae, Dong-Kuk Ahn
The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia...
May 2018: Korean Journal of Physiology & Pharmacology
https://www.readbyqxmd.com/read/29714131/functional-consequences-of-genetic-variation-in-sodium-channel-modifiers-in-early-onset-lone-atrial-fibrillation
#15
Federico Denti, Christian Paludan-Müller, Søren-Peter Olesen, Stig Haunsø, Jesper Hastrup Svendsen, Morten Salling Olesen, Bo Hjorth Bentzen, Nicole Schmitt
AIM: We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. PATIENTS & METHODS: Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. RESULTS: Co-expression of GPD1L or its p.A326E variant with NaV 1.5 did not alter INa density or current kinetics...
March 2018: Personalized Medicine
https://www.readbyqxmd.com/read/29708986/a-model-for-studying-the-energetics-of-sustained-high-frequency-firing
#16
Bela Joos, Michael R Markham, John E Lewis, Catherine E Morris
Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency...
2018: PloS One
https://www.readbyqxmd.com/read/29703751/gating-modifier-toxins-isolated-from-spider-venom-modulation-of-voltage-gated-sodium-channels-and-the-role-of-lipid-membranes
#17
Akello J Agwa, Steve Peigneur, Chun Yuen Chow, Nicole Lawrence, David J Craik, Jan Tytgat, Glenn F King, Sonia Troeira Henriques, Christina I Schroeder
Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures that modulate activity of disease-relevant voltage-gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here we examined whether there is a relationship among spider GMT amphipathicity, membrane binding and potency or selectivity for voltage-gated sodium (NaV) channels...
April 27, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29691040/progress-in-understanding-and-treating-scn2a-mediated-disorders
#18
REVIEW
Stephan J Sanders, Arthur J Campbell, Jeffrey R Cottrell, Rikke S Moller, Florence F Wagner, Angie L Auldridge, Raphael A Bernier, William A Catterall, Wendy K Chung, James R Empfield, Alfred L George, Joerg F Hipp, Omar Khwaja, Evangelos Kiskinis, Dennis Lal, Dheeraj Malhotra, John J Millichap, Thomas S Otis, Steven Petrou, Geoffrey Pitt, Leah F Schust, Cora M Taylor, Jennifer Tjernagel, John E Spiro, Kevin J Bender
Advances in gene discovery for neurodevelopmental disorders have identified SCN2A dysfunction as a leading cause of infantile seizures, autism spectrum disorder, and intellectual disability. SCN2A encodes the neuronal sodium channel NaV 1.2. Functional assays demonstrate strong correlation between genotype and phenotype. This insight can help guide therapeutic decisions and raises the possibility that ligands that selectively enhance or diminish channel function may improve symptoms. The well-defined function of sodium channels makes SCN2A an important test case for investigating the neurobiology of neurodevelopmental disorders more generally...
April 22, 2018: Trends in Neurosciences
https://www.readbyqxmd.com/read/29686617/a-chimeric-nav1-8-channel-expression-system-based-on-hek293t-cell-line
#19
Xi Zhou, Yunxiao Zhang, Dongfang Tang, Songping Liang, Ping Chen, Cheng Tang, Zhonghua Liu
Among the nine voltage-gated sodium channel (NaV) subtypes, NaV1.8 is an attractive therapeutic target for pain. The heterologous expression of recombinant NaV1.8 currents is of particular importance for its electrophysiological and pharmacological studies. However, NaV1.8 expresses no or low-level functional currents when transiently transfected into non-neuronal cell lines. The present study aims to explore the molecular determinants limiting its functional expression and accordingly establish a functional NaV1...
2018: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29684532/a-complicated-complex-ion-channels-voltage-sensing-cell-membranes-and-peptide-inhibitors
#20
REVIEW
Alan H Zhang, Gagan Sharma, Eivind A B Undheim, Xinying Jia, Mehdi Mobli
Voltage-gated ion channels (VGICs) are specialised ion channels that have a voltage dependent mode of action, where ion conduction, or gating, is controlled by a voltage-sensing mechanism. VGICs are critical for electrical signalling and are therefore important pharmacological targets. Among these, voltage-gated sodium channels (NaV s) have attracted particular attention as potential analgesic targets. NaV s, however, comprise several structurally similar subtypes with unique localisations and distinct functions, ranging from amplification of action potentials in nociception (e...
April 21, 2018: Neuroscience Letters
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