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https://www.readbyqxmd.com/read/28079757/pathogenesis-of-abdominal-pain-in-bowel-obstruction-role-of-mechanical-stress-induced-upregulation-of-nerve-growth-factor-in-gut-smooth-muscle-cells
#1
You-Min Lin, Yu Fu, John Winston, Ravi Radhakrishnan, Sushil K Sarna, Li-Yen M Huang, Xuan-Zheng Shi
Abdominal pain is one of the major symptoms in bowel obstruction (BO); its cellular mechanisms remain incompletely understood. We tested the hypothesis that mechanical stress in obstruction upregulates expression of nociception mediator nerve growth factor (NGF) in gut smooth muscle cells (SMC), and NGF sensitizes primary sensory nerve to contribute to pain in BO. Partial colon obstruction was induced with a silicon band implanted in the distal bowel of Sprague-Dawley rats. Colon-projecting sensory neurons in the dorsal root ganglia (DRG, T13 to L2) were identified for patch clamp and gene expression studies...
January 6, 2017: Pain
https://www.readbyqxmd.com/read/28074005/synergistic-regulation-of-serotonin-and-opioid-signaling-contributes-to-pain-insensitivity-in-nav1-7-knockout-mice
#2
Jörg Isensee, Leonhardt Krahé, Katharina Moeller, Vanessa Pereira, Jane E Sexton, Xiaohui Sun, Edward Emery, John N Wood, Tim Hucho
Genetic loss of the voltage-gated sodium channel Nav1.7 (Nav1.7(-/-)) results in lifelong insensitivity to pain in mice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Nav1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Nav1...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/28069705/multilevel-analyses-of-scn5a-mutations-in-arrhythmogenic-right-ventricular-dysplasia-cardiomyopathy-suggest-non-canonical-mechanisms-for-disease-pathogenesis
#3
Anneline S J M Te Riele, Esperanza Agullo-Pascual, Cynthia A James, Alejandra Leo-Macias, Marina Cerrone, Mingliang Zhang, Xianming Lin, Bin Lin, Nara L Sobreira, Nuria Amat-Alarcon, Roos F Marsman, Brittney Murray, Crystal Tichnell, Jeroen F van der Heijden, Dennis Dooijes, Toon A B van Veen, Harikrishna Tandri, Steven J Fowler, Richard N W Hauer, Gordon Tomaselli, Maarten P van den Berg, Matthew R G Taylor, Francesca Brun, Gianfranco Sinagra, Arthur A M Wilde, Luisa Mestroni, Connie R Bezzina, Hugh Calkins, J Peter van Tintelen, Lei Bu, Mario Delmar, Daniel P Judge
AIMS: Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) is often associated with desmosomal mutations. Recent studies suggest an interaction between the desmosome and sodium channel protein Nav1.5. We aimed to determine the prevalence and biophysical properties of mutations in SCN5A (the gene encoding Nav1.5) in ARVD/C. METHODS AND RESULTS: We performed whole-exome sequencing in six ARVD/C patients (33% male, 38.2 ± 12.1 years) without a desmosomal mutation...
January 2017: Cardiovascular Research
https://www.readbyqxmd.com/read/28065753/the-roles-of-conserved-aromatic-residues-tyr5-and-tyr42-in-interaction-of-scorpion-toxin-bmk-agp-sypu1-with-human-nav1-7
#4
Xiangxue Meng, Yijia Xu, Fangyang Wang, Mingyi Zhao, Xue Hou, Yuanyuan Ma, Yao Jin, Yanfeng Liu, Yongbo Song, Jinghai Zhang
Scorpion toxins are invaluable source of therapeutic leads and pharmacological tools which produce influence on the voltage gated sodium channels. In the previous study, our group has reported BmK AGP-SYPU1 (64 amino acids), one scorpion toxin with both potential α-type and β-type scorpion characteristics and analgesic activity in vivo, act as an activator to hNav1.4 and hNav1.5. Additionally, conserved aromatic amino acids Tyr5 and Tyr42 played important roles in bioactivity of BmK AGP-SYPU1 on hNav1.4 and hNav1...
January 5, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28045073/insensitivity-to-pain-induced-by-a-potent-selective-closed-state-nav1-7-inhibitor
#5
M Flinspach, Q Xu, A D Piekarz, R Fellows, R Hagan, A Gibbs, Y Liu, R A Neff, J Freedman, W A Eckert, M Zhou, R Bonesteel, M W Pennington, K A Eddinger, T L Yaksh, M Hunter, R V Swanson, A D Wickenden
Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1...
January 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28034736/cutaneous-iontophoresis-of-%C3%AE-conotoxin-cniiic-a-potent-nav1-4-antagonist-with-analgesic-anaesthetic-and-myorelaxant-properties
#6
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
#7
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/28017662/mechanism-of-inhibition-by-chlorpromazine-of-the-human-pain-threshold-sodium-channel-nav1-7
#8
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...
December 22, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/28009824/chitosan-oligosaccharide-reduces-propofol-requirements-and-propofol-related-side-effects
#9
Zhiwen Li, Xige Yang, Xuesong Song, Haichun Ma, Ping Zhang
Propofol is one of the main sedatives but its negative side effects limit its clinical application. Chitosan oligosaccharide (COS), a kind of natural product with anti-pain and anti-inflammatory activities, may be a potential adjuvant to propofol use. A total of 94 patients receiving surgeries were evenly and randomly assigned to two groups: 10 mg/kg COS oral administration and/or placebo oral administration before being injected with propofol. The target-controlled infusion of propofol was adjusted to maintain the values of the bispectral index at 50...
December 21, 2016: Marine Drugs
https://www.readbyqxmd.com/read/27998617/biophysical-molecular-and-pharmacological-characterization-of-voltage-dependent-sodium-channels-from-induced-pluripotent-stem-cell-derived-cardiomyocytes
#10
Adrien Moreau, Aurélie Mercier, Olivier Thériault, Mohamed Boutjdir, Bettina Burger, Dagmar I Keller, Mohamed Chahine
BACKGROUND: The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated Na(+) channel (Nav) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Nav channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Nav channels from hiPSC-CM and assess the appropriateness of this novel cell model...
October 11, 2016: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/27994738/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-and-pharmacokinetics-to-enable-in-vivo-target-engagement
#11
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
#12
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/27956748/association-of-rare-missense-variants-in-the-second-intracellular-loop-of-nav1-7-sodium-channels-with-familial-autism
#13
M Rubinstein, A Patowary, I B Stanaway, E McCord, R R Nesbitt, M Archer, T Scheuer, D Nickerson, W H Raskind, E M Wijsman, R Bernier, W A Catterall, Z Brkanac
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder often accompanied by intellectual disability, language impairment and medical co-morbidities. The heritability of autism is high and multiple genes have been implicated as causal. However, most of these genes have been identified in de novo cases. To further the understanding of familial autism, we performed whole-exome sequencing on five families in which second- and third-degree relatives were affected. By focusing on novel and protein-altering variants, we identified a small set of candidate genes...
December 13, 2016: Molecular Psychiatry
https://www.readbyqxmd.com/read/27940916/hierarchical-crmp2-posttranslational-modifications-control-nav1-7-function
#14
Erik T Dustrude, Aubin Moutal, Xiaofang Yang, Yuying Wang, May Khanna, Rajesh Khanna
Voltage-gated sodium channels are crucial determinants of neuronal excitability and signaling. Trafficking of the voltage-gated sodium channel NaV1.7 is dysregulated in neuropathic pain. We identify a trafficking program for NaV1.7 driven by hierarchical interactions with posttranslationally modified versions of the binding partner collapsin response mediator protein 2 (CRMP2). The binding described between CRMP2 and NaV1.7 was enhanced by conjugation of CRMP2 with small ubiquitin-like modifier (SUMO) and further controlled by the phosphorylation status of CRMP2...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27916648/nav1-7-as-a-pain-target-from-gene-to-pharmacology
#15
REVIEW
Irina Vetter, Jennifer R Deuis, Alexander Mueller, Mathilde R Israel, Hana Starobova, Alan Zhang, Lachlan D Rash, Mehdi Mobli
No abstract text is available yet for this article.
December 2, 2016: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/27916464/subtype-specific-block-of-voltage-gated-k-channels-by-%C3%AE-conopeptides
#16
Enrico Leipold, Florian Ullrich, Markus Thiele, Alesia A Tietze, Heinrich Terlau, Diana Imhof, Stefan H Heinemann
The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels. The related conopeptides μ-PIIIA and μ-SIIIA, however, exhibit a wider activity spectrum by also inhibiting the neuronal NaV channels NaV1.2 and NaV1.7. Here we demonstrate that those μ-conopeptides with a broader target range also antagonize select subtypes of voltage-gated potassium channels of the KV1 family: μ-PIIIA and μ-SIIIA inhibited KV1.1 and KV1.6 channels in the nanomolar range, while being inactive on subtypes KV1...
January 22, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27905525/inhibition-of-cystathionine-%C3%AE-synthetase-suppresses-sodium-channel-activities-of-dorsal-root-ganglion-neurons-of-rats-with-lumbar-disc-herniation
#17
Jun Yan, Shufen Hu, Kang Zou, Min Xu, Qianliang Wang, Xiuhua Miao, Shan Ping Yu, Guang-Yin Xu
The pathogenesis of pain in lumbar disc herniation (LDH) remains poorly understood. We have recently demonstrated that voltage-gated sodium channels (VGSCs) in dorsal root ganglion (DRG) neurons were sensitized in a rat model of LDH. However, the detailed molecular mechanism for sensitization of VGSCs remains largely unknown. This study was designed to examine roles of the endogenous hydrogen sulfide synthesizing enzyme cystathionine β-synthetase (CBS) in sensitization of VGSCs in a previously validated rat model of LDH...
December 1, 2016: Scientific Reports
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
#18
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/27871874/functional-and-immuno-reactive-characterization-of-a-previously-undescribed-peptide-from-the-venom-of-the-scorpion-centruroides-limpidus
#19
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
https://www.readbyqxmd.com/read/27821467/a-painful-neuropathy-associated-nav1-7-mutant-leads-to-time-dependent-degeneration-of-small-diameter-axons-associated-with-intracellular-ca2-dysregulation-and-decrease-in-atp-levels
#20
Harshvardhan Rolyan, Shujun Liu, Janneke Gj Hoeijmakers, Catharina G Faber, Ingemar Sj Merkies, Giuseppe Lauria, Joel A Black, Stephen G Waxman
Small fiber neuropathy is a painful sensory nervous system disorder characterized by damage to unmyelinated C- and thinly myelinated Aδ- nerve fibers, clinically manifested by burning pain in the distal extremities and dysautonomia. The clinical onset in adulthood suggests a time-dependent process. The mechanisms that underlie nerve fiber injury in small fiber neuropathy are incompletely understood, although roles for energetic stress have been suggested. In the present study, we report time-dependent degeneration of neurites from dorsal root ganglia neurons in culture expressing small fiber neuropathy-associated G856D mutant Nav1...
2016: Molecular Pain
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