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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
#1
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
#2
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
#3
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...
November 18, 2016: 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
#4
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
https://www.readbyqxmd.com/read/27815510/voltage-gated-sodium-channels-and-pain-related-disorders
#5
REVIEW
Alexandros H Kanellopoulos, Ayako Matsuyama
Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A-11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders...
December 1, 2016: Clinical Science (1979-)
https://www.readbyqxmd.com/read/27798132/gi-dreadd-expression-in-peripheral-nerves-produces-ligand-dependent-analgesia-as-well-as-ligand-independent-functional-changes-in-sensory-neurons
#6
Jami L Saloman, Nicole N Scheff, Lindsey M Snyder, Sarah E Ross, Brian M Davis, Michael S Gold
: Designer receptors exclusively activated by designer drugs (DREADDs) are an advanced experimental tool that could potentially provide a novel approach to pain management. In particular, expression of an inhibitory (Gi-coupled) DREADD in nociceptors might enable ligand-dependent analgesia. To test this possibility, TRPV1-cre mice were used to restrict expression of Gi-DREADDs to predominantly C-fibers. Whereas baseline heat thresholds in both male and female mice expressing Gi-DREADD were normal, 1 mg/kg clozapine-N-oxide (CNO) produced a significant 3 h increase in heat threshold that returned to baseline by 5 h after injection...
October 19, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/27777872/sodium-channel-nav1-7-expression-is-upregulated-in-the-dorsal-root-ganglia-in-a-rat-model-of-paclitaxel-induced-peripheral-neuropathy
#7
Zhongyuan Xia, Yun Xiao, Yang Wu, Bo Zhao
Paclitaxel-induced peripheral neuropathy is not completely known. Since the sodium channel Nav1.7 has been implicated in pain perception, and is upregulated in pain disorders, we investigated the effect of paclitaxel on Nav1.7 expression in rat dorsal root ganglion (DRG) neurons. Thirty Sprague-Dawley rats were administered either 2 mg/kg paclitaxel or vehicle on days 0, 2, 4 and 6. To evaluate nociceptive responses, paw withdrawal threshold (PWT) was measured by von Frey anesthesiometer on days 7, 14 and 21 after first paclitaxel administration...
2016: SpringerPlus
https://www.readbyqxmd.com/read/27765894/microrna-30b-regulates-expression-of-the-sodium-channel-nav1-7-in-nerve-injury-induced-neuropathic-pain-in-the-rat
#8
Jinping Shao, Jing Cao, Jiannan Wang, Xiuhua Ren, Songxue Su, Ming Li, Zhihua Li, Qingzan Zhao, Weidong Zang
Voltage-gated sodium channels, which are involved in pain pathways, have emerged as major targets for therapeutic intervention in pain disorders. Nav1.7, the tetrodotoxin-sensitive voltage-gated sodium channel isoform encoded by SCN9A and predominantly expressed in pain-sensing neurons in the dorsal root ganglion, plays a crucial role in nociception. MicroRNAs are highly conserved, small non-coding RNAs. Through binding to the 3' untranslated region of their target mRNAs, microRNAs induce the cleavage and/or inhibition of protein translation...
2016: Molecular Pain
https://www.readbyqxmd.com/read/27681629/early-somatic-mosaicism-is-a-rare-cause-of-long-qt-syndrome
#9
James Rush Priest, Charles Gawad, Kristopher M Kahlig, Joseph K Yu, Thomas O'Hara, Patrick M Boyle, Sridharan Rajamani, Michael J Clark, Sarah T K Garcia, Scott Ceresnak, Jason Harris, Sean Boyle, Frederick E Dewey, Lindsey Malloy-Walton, Kyla Dunn, Megan Grove, Marco V Perez, Norma F Neff, Richard Chen, Katsuhide Maeda, Anne Dubin, Luiz Belardinelli, John West, Christian Antolik, Daniela Macaya, Thomas Quertermous, Natalia A Trayanova, Stephen R Quake, Euan A Ashley
Somatic mosaicism, the occurrence and propagation of genetic variation in cell lineages after fertilization, is increasingly recognized to play a causal role in a variety of human diseases. We investigated the case of life-threatening arrhythmia in a 10-day-old infant with long QT syndrome (LQTS). Rapid genome sequencing suggested a variant in the sodium channel NaV1.5 encoded by SCN5A, NM_000335:c.5284G > T predicting p.(V1762L), but read depth was insufficient to be diagnostic. Exome sequencing of the trio confirmed read ratios inconsistent with Mendelian inheritance only in the proband...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27666479/trifluoperazine-blocks-the-human-cardiac-sodium-channel-nav1-5-independent-of-calmodulin
#10
Dong-Hyun Kim, Su-Jin Lee, Sang June Hahn, Jin-Sung Choi
Trifluoperazine is a phenothiazine derivative which is mainly used in the management of schizophrenia and also acts as a calmodulin inhibitor. We used the whole-cell patch-clamp technique to study the effects of trifluoperazine on human Nav1.5 (hNav1.5) currents expressed in HEK293 cells. The 50% inhibitory concentration of trifluoperazine was 15.5 ± 0.3 μM and the Hill coefficient was 2.7 ± 0.1. The effects of trifluoperazine on hNav1.5 were completely and repeatedly reversible after washout. Trifluoperazine caused depolarizing shifts in the activation and hyperpolarizing shifts in the steady-state inactivation of hNav1...
October 21, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27639908/-erythromelalgia-diagnosis-and-therapeutic-approach
#11
S Miranda, M Le Besnerais, V Langlois, Y Benhamou, H Lévesque
Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection...
September 14, 2016: La Revue de Médecine Interne
https://www.readbyqxmd.com/read/27608006/roles-of-voltage-gated-tetrodotoxin-sensitive-sodium-channels-nav1-3-and-nav1-7-in-diabetes-and-painful-diabetic-neuropathy
#12
REVIEW
Linlin Yang, Quanmin Li, Xinming Liu, Shiguang Liu
Diabetes mellitus (DM) is a common chronic medical problem worldwide; one of its complications is painful peripheral neuropathy, which can substantially erode quality of life and increase the cost of management. Despite its clinical importance, the pathogenesis of painful diabetic neuropathy (PDN) is complex and incompletely understood. Voltage-gated sodium channels (VGSCs) link many physiological processes to electrical activity by controlling action potentials in all types of excitable cells. Two isoforms of VGSCs, NaV1...
2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27598514/scn10a-mutation-in-a-patient-with-erythromelalgia-enhances-c-fiber-activity-dependent-slowing
#13
Andreas M Kist, Dagrun Sagafos, Anthony M Rush, Cristian Neacsu, Esther Eberhardt, Roland Schmidt, Lars Kristian Lunden, Kristin Ørstavik, Luisa Kaluza, Jannis Meents, Zhiping Zhang, Thomas Hedley Carr, Hugh Salter, David Malinowsky, Patrik Wollberg, Johannes Krupp, Inge Petter Kleggetveit, Martin Schmelz, Ellen Jørum, Angelika Lampert, Barbara Namer
Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations...
2016: PloS One
https://www.readbyqxmd.com/read/27587537/the-selective-nav1-7-inhibitor-pf-05089771-interacts-equivalently-with-fast-and-slow-inactivated-nav1-7-channels
#14
Jonathan W Theile, Matthew D Fuller, Mark L Chapman
Voltage-gated sodium (Nav) channel inhibitors are used clinically as analgesics and local anesthetics. However, the absence of Nav channel isoform selectivity of current treatment options can result in adverse cardiac and central nervous system side effects, limiting their therapeutic utility. Human hereditary gain- or loss-of-pain disorders have demonstrated an essential role of Nav1.7 sodium channels in the sensation of pain, thus making this channel an attractive target for new pain therapies. We previously identified a novel, state-dependent human Nav1...
November 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/27514860/shrna-mediated-knockdown-of-nav1-7-in-rat-dorsal-root-ganglion-attenuates-pain-following-burn-injury
#15
Weihua Cai, Jing Cao, Xiuhua Ren, Liang Qiao, Xuemei Chen, Ming Li, Weidong Zang
BACKGROUND: Abnormal acute pain after burn injury still torments patients severely. In this study, we investigated that one voltage gated sodium channel Nav1.7 plays a vital role in lowering heat pain threshold after burn injury, and the hypothesis that knockdown of Nav1.7 attenuates pain following burn injury. METHODS: Sixty eight adult male Sprague-Dawley rats were divided into 4 treatment groups: (1) sham, which hind paw was put on the room temperature metal plate for 15 s (2) burn model, which hind paw was put on the 85 °C metal plate for 15 s...
2016: BMC Anesthesiology
https://www.readbyqxmd.com/read/27514480/ion-channelopathies-in-functional-gi-disorders
#16
Arthur Beyder, Gianrico Farrugia
In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology...
October 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/27496104/a-gain-of-function-mutation-in-nav1-6-in-a-case-of-trigeminal-neuralgia
#17
Brian S Tanaka, Peng Zhao, Fadia B Dib-Hajj, Valerie Morisset, Simon Tate, Stephen G Waxman, Sulayman D Dib-Hajj
Idiopathic trigeminal neuralgia (TN) is a debilitating pain disorder characterized by episodic unilateral facial pain along the territory of branches of the trigeminal nerve. Human painful disorders, but not TN, have been linked to gain-of-function mutations in peripheral voltage-gated sodium channels (NaV1.7, NaV1.8 and NaV1.9). Gain-of-function mutations in NaV1.6, which is expressed in myelinated and unmyelinated CNS and peripheral nervous system neurons and supports neuronal high-frequency firing, have been linked to epilepsy but not to pain...
August 3, 2016: Molecular Medicine
https://www.readbyqxmd.com/read/27488668/activation-of-mek-erk-signaling-contributes-to-the-pacap-induced-increase-in-guinea-pig-cardiac-neuron-excitability
#18
John D Tompkins, Todd A Clason, Jean C Hardwick, Beatrice M Girard, Laura A Merriam, Victor May, Rodney L Parsons
Pituitary adenylate cyclase (PAC)-activating polypeptide (PACAP) peptides (Adcyap1) signaling at the selective PAC1 receptor (Adcyap1r1) participate in multiple homeostatic and stress-related responses, yet the cellular mechanisms underlying PACAP actions remain to be completely elucidated. PACAP/PAC1 receptor signaling increases excitability of neurons within the guinea pig cardiac ganglia, and as these neurons are readily accessible, this neuronal system is particularly amenable to study of PACAP modulation of ionic conductances...
October 1, 2016: American Journal of Physiology. Cell Physiology
https://www.readbyqxmd.com/read/27450927/oxidation-differentially-modulates-the-recombinant-voltage-gated-na-channel-%C3%AE-subunits-nav1-7-and-nav1-8
#19
Friederike Schlüter, Andreas Leffler
Voltage-gated Na(+) channels regulate neuronal excitability by generating the upstroke of action potentials. The α-subunits Nav1.7 and Nav1.8 are required for normal function of sensory neurons and thus for peripheral pain processing, but also for an increased excitability leading to an increased pain sensitivity under several conditions associated with oxidative stress. While little is known about the direct effects of oxidants on Nav1.7 and Nav1.8, a recent study on mouse dorsal root ganglion neurons suggested that oxidant-induced alterations of nociceptor excitability are primarily driven by Nav1...
October 1, 2016: Brain Research
https://www.readbyqxmd.com/read/27441383/application-of-a-parallel-synthetic-strategy-in-the-discovery-of-biaryl-acyl-sulfonamides-as-efficient-and-selective-nav1-7-inhibitors
#20
Erin F DiMauro, Stephen Altmann, Loren M Berry, Howard Bregman, Nagasree Chakka, Margaret Chu-Moyer, Elma Feric Bojic, Robert S Foti, Robert Fremeau, Hua Gao, Hakan Gunaydin, Angel Guzman-Perez, Brian E Hall, Hongbing Huang, Michael Jarosh, Thomas Kornecook, Josie Lee, Joseph Ligutti, Dong Liu, Bryan D Moyer, Daniel Ortuno, Paul E Rose, Laurie B Schenkel, Kristin Taborn, Jean Wang, Yan Wang, Violeta Yu, Matthew M Weiss
The majority of potent and selective hNaV1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNaV1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides...
September 8, 2016: Journal of Medicinal Chemistry
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