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Dongfang Tang, Zhen Xiao, Yan Xu, Jiao Zeng, Dezheng Peng, Songping Liang, Cheng Tang, Zhonghua Liu
Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaV s). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaV s in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaV s to the hyperpolarized direction...
February 28, 2018: Peptides
Lubin Chen, Jianying Huang, Peng Zhao, Anna-Karin Persson, Fadia B Dib-Hajj, Xiaoyang Cheng, Andrew Tan, Stephen G Waxman, Sulayman D Dib-Hajj
Voltage-gated sodium channels NaV 1.7, NaV 1.8 and NaV 1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV 1.6 in pain is less understood. In this study, we selectively knocked out NaV 1.6 in dorsal root ganglion (DRG) neurons, using NaV 1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV 1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain...
March 1, 2018: Scientific Reports
Kunsala T D S Yapa, Jennifer Deuis, Amelia A Peters, Paraic A Kenny, Sarah J Roberts-Thomson, Irina Vetter, Gregory R Monteith
AIMS: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. MATERIALS AND METHODS: Cell viability and migration of breast cancer cells was determined using MTS assays and wound healing assays, respectively. RNA-Seq analysis of breast tumours and qPCR in breast cancer cell lines were used to assess mRNA levels of ion channels...
February 26, 2018: Life Sciences
Jennifer J DeBerry, Vijay K Samineni, Bryan A Copits, Christopher J Sullivan, Sherri K Vogt, Kathryn M Albers, Brian M Davis, Robert W Gereau Iv
Bladder-innervating primary sensory neurons mediate reflex-driven bladder function under normal conditions, and contribute to debilitating bladder pain and/or overactivity in pathological states. The goal of this study was to examine the respective roles of defined subtypes of afferent neurons in bladder sensation and function in vivo via direct optogenetic activation. To accomplish this goal, we generated transgenic lines that express a Channelrhodopsin-2-eYFP fusion protein (ChR2-eYFP) in two distinct populations of sensory neurons: TRPV1-lineage neurons ( Trpv1 Cre ;Ai32, the majority of nociceptors) and Nav 1...
2018: Frontiers in Integrative Neuroscience
Tânia C Gonçalves, Rachid Boukaiba, Jordi Molgó, Muriel Amar, Michel Partiseti, Denis Servent, Evelyne Benoit
The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV 1.7 subtype of voltage-gated sodium (NaV ) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV 1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms...
February 20, 2018: Neuropharmacology
César Mattei
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain...
February 22, 2018: Marine Drugs
M Kollarik, H Sun, R A Herbstsomer, F Ru, M Kocmalova, S N Meeker, B J Undem
The action potential (AP) initiation in the nerve terminals and AP conduction along the axons do not necessarily depend on the same subtypes of Na V 1s. We evaluated the role of tetrodotoxin(TTX)-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Virtually all the jugular neurons expressed the TTX-sensitive channel Na V 1...
February 12, 2018: Journal of Physiology
Johannes Cip, Florian Obwegeser, Thomas Benesch, Christian Bach, Paul Ruckenstuhl, Arno Martin
BACKGROUND: Navigated computer-assisted total knee arthroplasty (TKA) was introduced to expedite long-term survival based on improved postoperative implantation accuracy. However, long-term outcome data after 10 years or more are rare, even available meta-analyses show controversial study results. METHODS: In a prospective randomized trial, 100 conventional TKAs (group CONV) were compared with 100 computer-assisted TKAs (group NAV) after a mean follow-up of 12 years postoperatively...
December 21, 2017: Journal of Arthroplasty
Dharmendra Singh Chauhan, Dilip Kumar Swain, Nadeem Shah, Hanuman Prasad Yadav, Abhishek Sharma, Brijesh Yadav, Sarvajeet Yadav, Rajesh Nigam, Satish Kumar Garg
In our previous study, we have reported the molecular presence of Nav 1.8 in bull spermatozoa and its potential involvement in regulation of sperm functions. With the selective blocking of Nav 1.8 using A-803467, alterations in sperm functions were observed, therefore, we envisaged of investigating the involvement of Nav in regulating sperm function and the mechanism(s) involved in it using veratridine, a selective opener of Nav channels. Forty ejaculates were collected from four Hariana bulls and semen samples were pooled in view of the non-significant variations between the different ejaculates...
November 27, 2017: Theriogenology
John Gilchrist, Frank Bosmans
Voltage-gated sodium (NaV ) channel gating is a complex phenomenon which involves a distinct contribution of four integral voltage-sensing domains (VSDI, VSDII, VSDIII and VSDIV). Utilizing accrued pharmacological and structural insights, we build on an established chimera approach to introduce animal toxin sensitivity in each VSD of an acceptor channel by transferring in portable S3b-S4 motifs from the four VSDs of a toxin-susceptible donor channel (NaV 1.2). By doing so, we observe that in NaV 1.8, a relatively unexplored channel subtype with distinctly slow gating kinetics, VSDI-III participate in channel opening whereas VSDIV can regulate opening as well as fast inactivation...
November 29, 2017: Journal of Physiology
Ying Wu, Hui Ma, Fan Zhang, Chunlei Zhang, Xiaohan Zou, Zhengyu Cao
Voltage-gated sodium channels (Navs) play critical roles in action potential generation and propagation. Nav channelopathy as well as pathological sensitization contribute to allodynia and hyperalgesia. Recent evidence has demonstrated the significant roles of Nav subtypes (Nav1.3, 1.7, 1.8, and 1.9) in nociceptive transduction, and therefore these Navs may represent attractive targets for analgesic drug discovery. Animal toxins are structurally diverse peptides that are highly potent yet selective on ion channel subtypes and therefore represent valuable probes to elucidate the structures, gating properties, and cellular functions of ion channels...
February 21, 2018: ACS Chemical Neuroscience
Yong-Yan Cai, Chen Li, Zhi-Xin Yan, Na Ma, Fang-Fang Li
The aim of the present study was to identify whether the sodium voltage-gated channel alpha subunit 9 (SCN9A) gene modification is a potential treatment for diarrhea‑predominant irritable bowel syndrome (D‑IBS), via regulating the Na+ channel and the expression of nerve growth factor (NGF). The recombinant adenovirus vector of the SCN9A gene was established, and rat colon cells were isolated for SCN9A gene modification. All subjects were divided into four groups: i) The SCN9A‑modified (D‑IBS rat model implanted with SCN9A‑modified colon cells), ii) negative control (NC; D‑IBS rat model implanted with colon cells without SCN9A gene modification), iii) blank (D‑IBS rat model without any treatment) and iv) normal (normal rats without any treatment)...
January 2018: Molecular Medicine Reports
Natasja Janssen, Roeland Eppenga, Marie-Jeanne Vrancken Peeters, Frederieke van Duijnhoven, Hester Oldenburg, Jos van der Hage, Emiel Rutgers, Jan-Jakob Sonke, Koert Kuhlmann, Theo Ruers, Jasper Nijkamp
PURPOSE: To evaluate a novel surgical navigation system for breast conserving surgery (BCS), based on real-time tumor tracking using the Calypso[Formula: see text] 4D Localization System (Varian Medical Systems Inc., USA). Navigation-guided breast conserving surgery (Nav-BCS) was compared to conventional iodine seed-guided BCS ([Formula: see text]I-BCS). METHODS: Two breast phantom types were produced, containing spherical and complex tumors in which wireless transponders (Nav-BCS) or a iodine seed ([Formula: see text]I-BCS) were implanted...
November 13, 2017: International Journal of Computer Assisted Radiology and Surgery
Kuan-Hung Chen, Chien-Hui Yang, Christopher Glenn Wallace, Chung-Ren Lin, Chia-Kai Liu, Tsung-Cheng Yin, Tien-Hung Huang, Yi-Ling Chen, Cheuk-Kwan Sun, Hon-Kan Yip
This study tested the hypothesis that combination therapy using extracorporeal shock wave (ECSW)-melatonin (Mel) was superior to either alone at ameliorating neuropathic pain (NP). NP was induced by chronic constriction injury (CCI) to the left sciatic nerve in rats. Animals were categorized into sham control (group 1), CCI only (group 2), CCI-ECSW (group 3), CCI-Mel (group 4) and CCI-ECSW-Mel (group 5). By days 2 and 8 after CCI, the mechanical paw withdrawal threshold (MPWT)/thermal paw withdrawal latency (TPWL) were highest in group 2, lowest in group 1, significantly lower in group 5 than in groups 3 and 4 (all p<0...
2017: American Journal of Translational Research
Jin Peng Du, Yong Fan, Qi Ning Wu, Dai Hua Wang, Jing Zhang, Ding Jun Hao
BACKGROUND: Many retrospective studies of pedicle screw placement have revealed that intraoperative navigation systems provide higher accuracy rates and safety than do free-hand techniques. The accuracy of various image-guided navigation systems has been studied; however, differences have not been well defined due to the lack of adequate evidence-based comparative studies. OBJECTIVE: A meta-analysis was conducted to focus on the variation in pedicle screw insertion among three navigation systems: a three-dimensional fluoroscopy-based navigation system (3D FluoroNav), a two-dimensional fluoroscopy-based navigation system (2D FluoroNav) and a conventional computed tomography navigation system (CT Nav)...
September 13, 2017: World Neurosurgery
Silmara R Sousa, Joshua S Wingerd, Andreas Brust, Christopher Bladen, Lotten Ragnarsson, Volker Herzig, Jennifer R Deuis, Sebastien Dutertre, Irina Vetter, Gerald W Zamponi, Glenn F King, Paul F Alewood, Richard J Lewis
Spider venoms are rich sources of peptidic ion channel modulators with important therapeutical potential. We screened a panel of 60 spider venoms to find modulators of ion channels involved in pain transmission. We isolated, synthesized and pharmacologically characterized Cd1a, a novel peptide from the venom of the spider Ceratogyrus darlingi. Cd1a reversibly paralysed sheep blowflies (PD50 of 1318 pmol/g) and inhibited human Cav2.2 (IC50 2.6 μM) but not Cav1.3 or Cav3.1 (IC50 > 30 μM) in fluorimetric assays...
2017: PloS One
Cristian González-Cabrera, Rodrigo Meza, Lorena Ulloa, Paulina Merino-Sepúlveda, Valentina Luco, Ana Sanhueza, Alejandro Oñate-Ponce, J Paul Bolam, Pablo Henny
The axon initial segment (AIS) is the site of initiation of action potentials and influences action potential waveform, firing pattern, and rate. In view of the fundamental aspects of motor function and behavior that depend on the firing of substantia nigra pars compacta (SNc) dopaminergic neurons, we identified and characterized their AIS in the mouse. Immunostaining for tyrosine hydroxylase (TH), sodium channels (Nav ) and ankyrin-G (Ank-G) was used to visualize the AIS of dopaminergic neurons. Reconstructions of sampled AIS of dopaminergic neurons revealed variable lengths (12-60 μm) and diameters (0...
July 22, 2017: Journal of Comparative Neurology
Mekhail Anwar, Annette M Molinaro, Olivier Morin, Susan M Chang, Daphne A Haas-Kogan, Sarah J Nelson, Janine M Lupo
Despite the longstanding role of radiation in cancer treatment and the presence of advanced, high-resolution imaging techniques, delineation of voxels at-risk for progression remains purely a geometric expansion of anatomic images, missing subclinical disease at risk for recurrence while treating potentially uninvolved tissue and increasing toxicity. This remains despite the modern ability to precisely shape radiation fields. A striking example of this is the treatment of glioblastoma, a highly infiltrative tumor that may benefit from accurate identification of subclinical disease...
September 2017: Radiation Research
Hui Sun, Marian Kollarik, Bradley J Undem
Pathological cough is thought to be secondary to inappropriate activation of vagal sensory nerves. Sensory nerves can be activated by a large number of disparate stimuli. The most relevant stimuli to block for effective anti-tussive therapy likely depend on the specific underlying pathology that is leading to the coughing. Blocking voltage-gated sodium channels (NaV) will prevent action potential initiation and conduction and therefore prevent sensory communication between the airways and brainstem. In so doing, they would be expected to inhibit evoked cough independently of the nature of the stimulus and underlying pathology...
May 15, 2017: Pulmonary Pharmacology & Therapeutics
Thomas J Kornecook, Ruoyuan Yin, Stephen Altmann, Xuhai Be, Virginia Berry, Christopher P Ilch, Michael Jarosh, Danielle Johnson, Josie H Lee, Sonya G Lehto, Joseph Ligutti, Dong Liu, Jason Luther, David Matson, Danny Ortuno, John Roberts, Kristin Taborn, Jinti Wang, Matthew M Weiss, Violeta Yu, Dawn X D Zhu, Robert T Fremeau, Bryan D Moyer
Potent and selective antagonists of the voltage-gated sodium channel NaV1.7 represent a promising avenue for the development of new chronic pain therapies. We generated a small molecule atropisomer quinolone sulfonamide antagonist AMG8379 and a less active enantiomer AMG8380. Here we show that AMG8379 potently blocks human NaV1.7 channels with an IC50 of 8.5 nM and endogenous tetrodotoxin (TTX)-sensitive sodium channels in dorsal root ganglion (DRG) neurons with an IC50 of 3.1 nM in whole-cell patch clamp electrophysiology assays using a voltage protocol that interrogates channels in a partially inactivated state...
July 2017: Journal of Pharmacology and Experimental Therapeutics
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