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https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#1
Sassan Rahnama, Jennifer R Deuis, Fernanda C Cardoso, Venkatraman Ramanujam, Richard J Lewis, Lachlan D Rash, Glenn F King, Irina Vetter, Mehdi Mobli
Venom-derived peptides have attracted much attention as potential lead molecules for pharmaceutical development. A well-known example is Huwentoxin-IV (HwTx-IV), a peptide toxin isolated from the venom of the Chinese bird-eating spider Haplopelma schmitdi. HwTx-IV was identified as a potent blocker of a human voltage-gated sodium channel (hNaV1.7), which is a genetically validated analgesic target. The peptide was promising as it showed high potency at NaV1.7 (IC50 ~26 nM) and selectivity over the cardiac NaV subtype (NaV1...
2017: PloS One
https://www.readbyqxmd.com/read/28300672/discovery-of-three-toxin-peptides-with-kv1-3-channel-and-il-2-cytokine-inhibiting-activities-from-non-buthidae-scorpions-chaerilus-tricostatus-and-chaerilus-tryznai
#2
Li Ding, Jing Chen, Jinbo Hao, Jiahui Zhang, Xuejun Huang, Fangfang Hu, Zheng Wu, Yaru Liu, Wenxin Li, Zhijian Cao, Yingliang Wu, Jian Li, Shan Li, Hongyan Liu, Wenlong Wu, Zongyun Chen
Non-Buthidae venomous scorpions are huge natural sources of toxin peptides; however, only a few studies have been done to understand their toxin peptides. Herein, we describe three new potential immunomodulating toxin peptides, Ctri18, Ctry68 and Ctry2908, from two non-Buthidae scorpions, Chaerilus tricostatus and Chaerilus tryznai. Sequence alignment analyses showed that Ctri18, Ctry68 and Ctry2908 are three new members of the scorpion toxin α-KTx15 subfamily. Electrophysiological experiments showed that Ctri18, Ctry68 and Ctry2908 blocked the Kv1...
March 12, 2017: Peptides
https://www.readbyqxmd.com/read/28298073/electro-acupuncture-modulated-mir-214-prevents-neuronal-apoptosis-by-targeting-bax-and-inhibits-sodium-channel-nav1-3-expression-in-rats-after-spinal-cord-injury
#3
Jing Liu, Yaochi Wu
Electro-acupuncture (EA) has been proven to contribute towards neurologic and functional recoveries in spinal cord injury (SCI), but the underlying mechanism remains largely unknown especially regarding the effects of preventing neuronal apoptosis and alleviating neuropathic pain involved in the development of EA. In this study, we evaluated the effect of EA treatment in an animal model of SCI using the Basso, Beattie, and Bresnahan (BBB) score method, lesion volume by cresyl violet staining and neuronal apoptosis by TUNEL staining...
March 11, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28279058/-preliminary-study-on-the-role-of-voltage-gated-sodium-channel-subtype-nav1-5-in-lymph-node-metastasis-of-oral-squamous-cell-carcinoma
#4
W J Liu, L Xu, X W Zhu, X F Chen, H Wang, Y Jiang
Objective: To investigate the relationship between the expression of voltage-gated sodium channel subtype Nav1.5 in oral squamous cell carcinoma (OSCC) and the occurrence and lymph node metastasis of OSCC. Methods: Totally 10 samples of normal oral mucosa tissue as control group, 26 samples of OSCC as the experimental group was divided into non-metastatic group (n=16) and metastatic group (n=10) according to the presence or absence of lymph node metastasis. Quantitative real-time PCR (qPCR), Western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to detect the expression of Nav1...
March 9, 2017: Zhonghua Kou Qiang Yi Xue za Zhi, Zhonghua Kouqiang Yixue Zazhi, Chinese Journal of Stomatology
https://www.readbyqxmd.com/read/28266963/safety-and-efficacy-of-a-topical-sodium-channel-inhibitor-tv-45070-in-patients-with-postherpetic-neuralgia-phn-a-randomized-controlled-proof-of-concept-crossover-study-with-a-subgroup-analysis-of-the-nav1-7-r1150w-genotype
#5
Nicola Price, Rostam Namdari, Judith Neville, Katie J W Proctor, Samer Kaber, Jeffery Vest, Michael Fetell, Richard Malamut, Robin P Sherrington, Simon N Pimstone, Yigal P Goldberg
OBJECTIVE: The objective was to evaluate the safety and efficacy of TV-45070 ointment, as a treatment for postherpetic neuralgia, and to explore the response in patients with the Nav1.7 R1150W gain-of-function polymorphism. MATERIALS AND METHODS: This was a randomized, placebo-controlled, 2-period, 2-treatment crossover trial. Patients with postherpetic neuralgia with moderate or greater pain received TV-45070 and placebo ointments, each applied twice daily for 3 weeks...
April 2017: Clinical Journal of Pain
https://www.readbyqxmd.com/read/28255076/beneficial-effect-of-renal-denervation-on-ventricular-premature-complex-induced-cardiomyopathy
#6
Shinya Yamada, Li-Wei Lo, Yu-Hui Chou, Wei-Lun Lin, Shih-Lin Chang, Yenn-Jiang Lin, Shin-Huei Liu, Wen-Han Cheng, Tsung-Ying Tsai, Shih-Ann Chen
BACKGROUND: Frequent ventricular premature complexes (VPCs) can lead to the development of dilated cardiomyopathy and sudden cardiac death. Renal artery sympathetic denervation (RDN) may protect the heart from remodeling. This study aimed to investigate the effect of frequent VPCs on structural and electrical properties and whether RDN can protect the heart from remodeling. METHODS AND RESULTS: Eighteen rabbits were randomized to control (n=6), VPC (n=6), and VPC-RDN (n=6) groups...
March 2, 2017: Journal of the American Heart Association
https://www.readbyqxmd.com/read/28235671/scn3a-deficiency-associated-with-increased-seizure-susceptibility
#7
Tyra Lamar, Carlos G Vanoye, Jeffrey Calhoun, Jennifer C Wong, Stacey B B Dutton, Benjamin S Jorge, Milen Velinov, Andrew Escayg, Jennifer A Kearney
Mutations in voltage-gated sodium channels expressed highly in the brain (SCN1A, SCN2A, SCN3A, and SCN8A) are responsible for an increasing number of epilepsy syndromes. In particular, mutations in the SCN3A gene, encoding the pore-forming Nav1.3 α subunit, have been identified in patients with focal epilepsy. Biophysical characterization of epilepsy-associated SCN3A variants suggests that both gain- and loss-of-function SCN3A mutations may lead to increased seizure susceptibility. In this report, we identified a novel SCN3A variant (L247P) by whole exome sequencing of a child with focal epilepsy, developmental delay, and autonomic nervous system dysfunction...
February 22, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#8
Ying Wu, Beiyan Zou, Lingli Liang, Min Li, Yuan-Xiang Tao, Haibo Yu, Xiaoliang Wang, Min Li
Previous studies demonstrated that Loperamide, originally known as an anti-diarrheal drug, is a promising analgesic agent primarily targeting mu-opioid receptors. However some evidences suggested that non-opioid mechanisms may be contributing to its analgesic effect. In the present study, Loperamide was identified as a Nav1.7 blocker in a pilot screen. In HEK293 cells expressing Nav1.7 sodium channels, Loperamide blocked the resting state of Nav1.7 channels (IC50 = 1.86 ± 0.11 μM) dose-dependently and reversibly...
February 16, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28213505/revealing-the-concealed-nature-of-long-qt-type-3-syndrome
#9
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/28166971/functional-and-molecular-characterization-of-voltage-gated-sodium-channel-nav-1-8-in-bull-spermatozoa
#10
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/28138042/control-of-neurotransmission-by-nav1-7-in-human-guinea-pig-and-mouse-airway-parasympathetic-nerves
#11
Michaela Kocmalova, Marian Kollarik, Brendan J Canning, Fei Ru, Robert A Herbstromer, Sonya Meeker, Silvia Fonquerna, Monica Aparici, Montserrat Miralpeix, Xian Chi, Baolin Li, Ben Wilenkin, Jeff McDermott, Eric Nisenbaum, Jeff Krajewski, Bradley J Undem
Little is known about the voltage-gated sodium channels (NaVs) that control neurotransmission in the parasympathetic nervous system. We evaluated the expression of the α subunits of each of the nine NaVs in human, guinea pig, and mouse airway parasympathetic ganglia. We combined this information with a pharmacological analysis of selective NaV blockers on parasympathetic contractions of isolated airway smooth muscle. As would be expected from previous studies, tetrodotoxin potently blocked the parasympathetic responses in the airways of each species...
January 30, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28117367/the-sorting-receptor-rer1-controls-purkinje-cell-function-via-voltage-gated-sodium-channels
#12
Christina Valkova, Lutz Liebmann, Andreas Krämer, Christian A Hübner, Christoph Kaether
Rer1 is a sorting receptor in the early secretory pathway that controls the assembly and the cell surface transport of selected multimeric membrane protein complexes. Mice with a Purkinje cell (PC) specific deletion of Rer1 showed normal polarization and differentiation of PCs and normal development of the cerebellum. However, PC-specific loss of Rer1 led to age-dependent motor deficits in beam walk, ladder climbing and gait. Analysis of brain sections revealed a specific degeneration of PCs in the anterior cerebellar lobe in old animals...
January 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28115552/xenin-augments-duodenal-anion-secretion-via-activation-of-afferent-neural-pathways
#13
Izumi Kaji, Yasutada Akiba, Ikuo Kato, Koji Maruta, Atsukazu Kuwahara, Jonathan D Kaunitz
Xenin-25, a neurotensin (NT)-related anorexigenic gut hormone generated mostly in the duodenal mucosa, is believed to increase the rate of duodenal ion secretion, since xenin-induced diarrhea is not present after Roux-en-Y gastric bypass surgery. Since the local effects of xenin on duodenal ion secretion have remained uninvestigated, we thus examined the neural pathways underlying xenin-induced duodenal anion secretion. Intravenous infusion of xenin-8, a bioactive C-terminal fragment of xenin-25, dose-dependently increased the rate of duodenal HCO3- secretion in perfused duodenal loops of anesthetized rats...
January 23, 2017: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/28100740/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#14
Zachary Niday, Virginia E Hawkins, Heun Soh, Daniel K Mulkey, Anastasios V Tzingounis
KCNQ2 potassium channels are critical for normal brain function, as both loss-of-function and gain-of-function KCNQ2 variants can lead to various forms of neonatal epilepsy. Despite recent progress, the full spectrum of consequences as a result of KCNQ2 dysfunction in neocortical pyramidal neurons is still unknown. Here, we report that conditional ablation of Kcnq2 from mouse neocortex leads to hyperexcitability of layer 2/3 (L2/3) pyramidal neurons, exhibiting an increased input resistance and action potential frequency, as well as a reduced medium afterhyperpolarization (mAHP), a conductance partly mediated by KCNQ2 channels...
January 18, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28034736/cutaneous-iontophoresis-of-%C3%AE-conotoxin-cniiic-a-potent-nav1-4-antagonist-with-analgesic-anaesthetic-and-myorelaxant-properties
#15
Sergio Del Río-Sancho, Cecile Cros, Bethsabée Coutaz, Muriel Cuendet, Yogeshvar N Kalia
Cutaneous iontophoretic delivery of μ-conotoxin CnIIIC (XEP), a potent peptide antagonist of the NaV1.4 sodium channel, was investigated using porcine ear skin and validated using human abdominal skin. Initial results demonstrated that cutaneous deposition of XEP following iontophoresis was superior to passive delivery and increased with current density. XEP deposition after iontophoresis at 0.1, 0.3 and 0.5mA/cm(2) for 2h and 4h was 22.4±0.4, 34.5±1.4, 57.4±7.6μg/cm(2) and 30.6±5.4, 53.9±17.2, 90.9±30...
December 26, 2016: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28026020/low-pho-boosts-burst-firing-and-catecholamine-release-by-blocking-task-1-and-bk-channels-while-preserving-cav1-channels-in-mouse-chromaffin-cells
#16
Laura Guarina, David H F Vandael, Valentina Carabelli, Emilio Carbone
Mouse chromaffin cells (MCCs) generate action potential (AP) firing that regulates the Ca(2+) -dependent release of catecholamines (CAs). Recent findings indicate that MCCs possess a variety of spontaneous firing modes that span from the common "tonic-irregular" to the less frequent "burst" firing. This latter is evident in a small fraction of MCCs but occurs regularly when Nav1.3/1.7 channels are made less available or when the Slo1β2-subunit responsible for BK channel inactivation is deleted. Burst firing causes massive increases of Ca(2+) -entry and potentiates CA release ∼3...
December 27, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/28025109/deet-potentiates-the-development-and-persistence-of-anticholinesterase-dependent-chronic-pain-signs-in-a-rat-model-of-gulf-war-illness-pain
#17
L K Flunker, T J Nutter, R D Johnson, B Y Cooper
Exposure to DEET (N,N-diethyl-meta-toluamide) may have influenced the pattern of symptoms observed in soldiers with GWI (Gulf War Illness; Haley and Kurt, 1997). We examined how the addition of DEET (400mg/kg; 50% topical) to an exposure protocol of permethrin (2.6mg/kg; topical), chlorpyrifos (CP; 120mg/kg), and pyridostigmine bromide (PB;13mg/kg) altered the emergence and pattern of pain signs in an animal model of GWI pain (Nutter et al., 2015). Rats underwent behavioral testing before, during and after a 4week exposure: 1) hindlimb pressure withdrawal threshold; 2) ambulation (movement distance and rate); and 3) resting duration...
December 23, 2016: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28017662/mechanism-of-inhibition-by-chlorpromazine-of-the-human-pain-threshold-sodium-channel-nav1-7
#18
Su-Jin Lee, Dong-Hyun Kim, Sang June Hahn, Stephen G Waxman, Jin-Sung Choi
Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Nav1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Nav1.7 (hNav1.7) sodium current in HEK293 cells stably expressing hNav1.7 using the whole-cell patch-clamp technique. The peak current of hNav1.7 was reduced by chlorpromazine in a concentration-dependent manner with a half-maximal inhibitory concentration of 25.9±0.6μM and a Hill coefficient of 2...
February 3, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/27994738/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-to-enable-in-vivo-target-engagement
#19
Isaac E Marx, Thomas A Dineen, Jessica Able, Christiane Bode, Howard Bregman, Margaret Chu-Moyer, Erin F DiMauro, Bingfan Du, Robert S Foti, Robert T Fremeau, Hua Gao, Hakan Gunaydin, Brian E Hall, Liyue Huang, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Jeff S McDermott, Bryan D Moyer, Emily A Peterson, Jonathan T Roberts, Paul Rose, Jean Wang, Beth D Youngblood, Violeta Yu, Matthew M Weiss
Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing...
December 8, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27994149/fgf14-is-a-regulator-of-kcnq2-3-channels
#20
Juan Lorenzo Pablo, Geoffrey S Pitt
KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we show that fibroblast growth factor 14 (FGF14), previously described as a VGSC regulator, also affects KCNQ function and localization...
January 3, 2017: Proceedings of the National Academy of Sciences of the United States of America
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