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https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
#12
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
#13
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
https://www.readbyqxmd.com/read/27989687/role-of-protein-kinase-c-in-metabolic-regulation-of-the-cardiac-na-channel
#14
Man Liu, Guangbin Shi, Kai-Chien Yang, Lianzhi Gu, Anumantha G Kanthasamy, Vellareddy Anantharam, Samuel C Dudley
BACKGROUND: The reduced form of nicotinamide adenine dinucleotide (NADH) increases in cardiomyopathy, activates protein kinase C (PKC), up-regulates mitochondrial reactive oxygen species (mitoROS), and down-regulates the cardiac Na(+) channel (NaV1.5). OBJECTIVE: The purpose of this study was to determine how NADH signals down-regulation of NaV1.5. METHODS: Isolated mouse cardiomyocytes were used for patch-clamp recording and for monitoring mitoROS with MitoSOX Red...
December 15, 2016: Heart Rhythm: the Official Journal of the Heart Rhythm Society
https://www.readbyqxmd.com/read/27920148/epilepsy-associated-kcnq2-channels-regulate-multiple-intrinsic-properties-of-layer-2-3-pyramidal-neurons
#15
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- 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...
December 5, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27896032/gene-expression-profile-of-sodium-channel-subunits-in-the-anterior-cingulate-cortex-during-experimental-paclitaxel-induced-neuropathic-pain-in-mice
#16
Willias Masocha
Paclitaxel, a chemotherapeutic agent, causes neuropathic pain whose supraspinal pathophysiology is not fully understood. Dysregulation of sodium channel expression, studied mainly in the periphery and spinal cord level, contributes to the pathogenesis of neuropathic pain. We examined gene expression of sodium channel (Nav) subunits by real time polymerase chain reaction (PCR) in the anterior cingulate cortex (ACC) at day 7 post first administration of paclitaxel, when mice had developed paclitaxel-induced thermal hyperalgesia...
2016: PeerJ
https://www.readbyqxmd.com/read/27882143/expression-of-connexin-43-ion-channels-and-ca-2-handling-proteins-in-rat-pulmonary-vein-cardiomyocytes
#17
Yaqiong Xiao, Xue Cai, Andrew Atkinson, Sunil Jit Logantha, Mark Boyett, Halina Dobrzynski
Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF is thought to be triggered by ectopic beats, originating primarily in the myocardial sleeves surrounding the pulmonary veins (PVs). The mechanisms underlying these cardiac arrhythmias remain unclear. To investigate this, frozen sections of heart and lung tissue from adult rats without arrhythmia were obtained in different planes, stained with Masson's trichrome, and immunolabeled for connexin 43 (Cx43), caveolin-3 (Cav3), hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4), Nav1...
November 2016: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/27882075/in-silico-evaluation-of-the-potential-antiarrhythmic-effect-of-epigallocatechin-3-gallate-on-cardiac-channelopathies
#18
Maroua Boukhabza, Jaouad El Hilaly, Nourdine Attiya, Ahmed El-Haidani, Younes Filali-Zegzouti, Driss Mazouzi, Mohamed-Yassine Amarouch
Ion channels are transmembrane proteins that allow the passage of ions according to the direction of their electrochemical gradients. Mutations in more than 30 genes encoding ion channels have been associated with an increasingly wide range of inherited cardiac arrhythmias. In this line, ion channels become one of the most important molecular targets for several classes of drugs, including antiarrhythmics. Nevertheless, antiarrhythmic drugs are usually accompanied by some serious side effects. Thus, developing new approaches could offer added values to prevent and treat the episodes of arrhythmia...
2016: Computational and Mathematical Methods in Medicine
https://www.readbyqxmd.com/read/27879566/the-effect-of-an-acid-sensing-ion-channels-asics-inhibitor-on-pain-related-behavior-by-nucleus-pulposus-applied-on-the-nerve-root-in-rats
#19
Yoshihiro Kobayashi, Miho Sekiguchi, Shin-Ichi Konno
STUDY DESIGN: Controlled, interventional, animal study. OBJECTIVE: To examine the effect of an inhibitor of acid-sensing ion channel 3 (ASIC3) on pain-related behavior induced by application of the nucleus pulposus (NP) onto the dorsal root ganglion (DRG) in rats. SUMMARY OF BACKGROUND DATA: ASIC3 is associated with acidosis pain in inflamed or ischemic tissues and is expressed in sensory neurons and NP cells. The ASIC3 inhibitor, APETx2, increases the mechanical threshold of pain in models of knee osteoarthritis or postoperative pain...
November 22, 2016: Spine
https://www.readbyqxmd.com/read/27871874/functional-and-immuno-reactive-characterization-of-a-previously-undescribed-peptide-from-the-venom-of-the-scorpion-centruroides-limpidus
#20
Timoteo Olamendi-Portugal, Rita Restano-Cassulini, Lidia Riaño-Umbarila, Baltazar Becerril, Lourival D Possani
A previously undescribed toxic peptide named Cl13 was purified from the venom of the Mexican scorpion Centruroides limpidus. It contains 66 amino acid residues, including four disulfide bonds. The physiological effects assayed in 7 different subtypes of voltage gated Na(+)-channels, showed that it belongs to the β-scorpion toxin type. The most notorious effects were observed in subtypes Nav1.4, Nav1.5 and Nav1.6. Although having important sequence similarities with two other lethal toxins from this scorpion species (Cll1m and Cll2), the recently developed single chain antibody fragments (scFv) of human origin were not capable of protecting against Cl13...
January 2017: Peptides
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