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https://www.readbyqxmd.com/read/28324649/sulfonamides-as-selective-nav1-7-inhibitors-optimizing-potency-pharmacokinetics-and-metabolic-properties-to-obtain-atropisomeric-quinolinone-am-0466-that-affords-robust-in-vivo-activity
#1
Russell F Graceffa, Alessandro A Boezio, Jessica Able, Steven Altmann, Loren M Berry, Christiane M Boezio, John R Butler, Margaret Y Chu-Moyer, Melanie Cooke, Erin F DiMauro, Thomas A Dineen, Elma Feric Bojic, Robert S Foti, Robert T Fremeau, Angel Guzman-Perez, Hua Gao, Hakan Gunaydin, Hongbing Huang, Liyue Huang, Christopher Ilch, Michael Jarosh, Thomas Kornecook, Charles R Kreiman, Daniel S La, Joseph Ligutti, Benjamin Charles Milgram, Min-Hwa Jasmine Lin, Isaac E Marx, Hanh Nho Nguyen, Emily A Peterson, Gwen Rescourio, John Roberts, Laurie B Schenkel, Roman Shimanovich, Brian Andrew Sparling, John Stellwagen, Kristin Taborn, Karina R Vaida, Jean Wang, John T S Yeoman, Violeta L Yu, Dawn Zhu, Bryan D Moyer, Matthew M Weiss
Due to its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaV isoforms. Herein, we report the discovery and optimization of a novel series of atropisomeric quinolinone sulfonamide inhibitors of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms...
March 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28318976/assembly-of-cns-nodes-of-ranvier-in-myelinated-nerves-is-promoted-by-the-axon-cytoskeleton
#2
Veronica Brivio, Catherine Faivre-Sarrailh, Elior Peles, Diane L Sherman, Peter J Brophy
Nodes of Ranvier in the axons of myelinated neurons are exemplars of the specialized cell surface domains typical of polarized cells. They are rich in voltage-gated sodium channels (Nav) and thus underpin rapid nerve impulse conduction in the vertebrate nervous system [1]. Although nodal proteins cluster in response to myelination, how myelin-forming glia influence nodal assembly is poorly understood. An axoglial adhesion complex comprising glial Neurofascin155 and axonal Caspr/Contactin flanks mature nodes [2]...
March 11, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#3
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/28241082/modeling-of-the-axon-membrane-skeleton-structure-and-implications-for-its-mechanical-properties
#4
Yihao Zhang, Krithika Abiraman, He Li, David M Pierce, Anastasios V Tzingounis, George Lykotrafitis
Super-resolution microscopy recently revealed that, unlike the soma and dendrites, the axon membrane skeleton is structured as a series of actin rings connected by spectrin filaments that are held under tension. Currently, the structure-function relationship of the axonal structure is unclear. Here, we used atomic force microscopy (AFM) to show that the stiffness of the axon plasma membrane is significantly higher than the stiffnesses of dendrites and somata. To examine whether the structure of the axon plasma membrane determines its overall stiffness, we introduced a coarse-grain molecular dynamics model of the axon membrane skeleton that reproduces the structure identified by super-resolution microscopy...
February 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28225079/multiple-sodium-channel-isoforms-mediate-the-pathological-effects-of-pacific-ciguatoxin-1
#5
Marco C Inserra, Mathilde R Israel, Ashlee Caldwell, Joel Castro, Jennifer R Deuis, Andrea M Harrington, Angelo Keramidas, Sonia Garcia-Caraballo, Jessica Maddern, Andelain Erickson, Luke Grundy, Grigori Y Rychkov, Katharina Zimmermann, Richard J Lewis, Stuart M Brierley, Irina Vetter
Human intoxication with the seafood poison ciguatoxin, a dinoflagellate polyether that activates voltage-gated sodium channels (NaV), causes ciguatera, a disease characterised by gastrointestinal and neurological disturbances. We assessed the activity of the most potent congener, Pacific ciguatoxin-1 (P-CTX-1), on NaV1.1-1.9 using imaging and electrophysiological approaches. Although P-CTX-1 is essentially a non-selective NaV toxin and shifted the voltage-dependence of activation to more hyperpolarising potentials at all NaV subtypes, an increase in the inactivation time constant was observed only at NaV1...
February 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28220076/actions-and-mechanisms-of-polyunsaturated-fatty-acids-on-voltage-gated-ion-channels
#6
REVIEW
Fredrik Elinder, Sara I Liin
Polyunsaturated fatty acids (PUFAs) act on most ion channels, thereby having significant physiological and pharmacological effects. In this review we summarize data from numerous PUFAs on voltage-gated ion channels containing one or several voltage-sensor domains, such as voltage-gated sodium (NaV), potassium (KV), calcium (CaV), and proton (HV) channels, as well as calcium-activated potassium (KCa), and transient receptor potential (TRP) channels. Some effects of fatty acids appear to be channel specific, whereas others seem to be more general...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28216001/loperamide-inhibits-sodium-channels-to-alleviate-inflammatory-hyperalgesia
#7
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/28214515/igg-degrading-enzyme-of-streptococcus-pyogenes-ides-prevents-disease-progression-and-facilitates-improvement-in-a-rabbit-model-of-guillain-barr%C3%A3-syndrome
#8
Yuzhong Wang, Qiguang Shi, Hui Lv, Ming Hu, Weifang Wang, Quanquan Wang, Baojun Qiao, Guorong Zhang, Zhanyun Lv, Christian Kjellman, Sofia Järnum, Lena Winstedt, Yong Zhang, Jiao Wen, Yanlei Hao, Nobuhiro Yuki
Autoantibodies binding to peripheral nerves followed by complement deposition and membrane attack complex formation results in nerve damage in Guillain-Barré syndrome (GBS). Strategies to remove the pathogenic autoantibodies or block the complement deposition benefit most patients with GBS. Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) is a cysteine protease which cleaves IgG antibodies into F(ab')2 and Fc fragments. In this study, using a rabbit model of axonal GBS, acute motor axonal neuropathy (AMAN), we demonstrated that IdeS treatment significantly reduced the disruption of Nav channels as well as activated C3 deposition at the anterior spinal root nodes of Ranvier in AMAN rabbits...
February 16, 2017: Experimental Neurology
https://www.readbyqxmd.com/read/28205548/the-complete-structure-of-an-activated-open-sodium-channel
#9
Altin Sula, Jennifer Booker, Leo C T Ng, Claire E Naylor, Paul G DeCaen, B A Wallace
Voltage-gated sodium channels (Navs) play essential roles in excitable tissues, with their activation and opening resulting in the initial phase of the action potential. The cycling of Navs through open, closed and inactivated states, and their closely choreographed relationships with the activities of other ion channels lead to exquisite control of intracellular ion concentrations in both prokaryotes and eukaryotes. Here we present the 2.45 Å resolution crystal structure of the complete NavMs prokaryotic sodium channel in a fully open conformation...
February 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28202723/mapping-of-voltage-sensor-positions-in-resting-and-inactivated-mammalian-sodium-channels-by-lret
#10
Tomoya Kubota, Thomas Durek, Bobo Dang, Rocio K Finol-Urdaneta, David J Craik, Stephen B H Kent, Robert J French, Francisco Bezanilla, Ana M Correa
Voltage-gated sodium channels (Navs) play crucial roles in excitable cells. Although vertebrate Nav function has been extensively studied, the detailed structural basis for voltage-dependent gating mechanisms remain obscure. We have assessed the structural changes of the Nav voltage sensor domain using lanthanide-based resonance energy transfer (LRET) between the rat skeletal muscle voltage-gated sodium channel (Nav1.4) and fluorescently labeled Nav1.4-targeting toxins. We generated donor constructs with genetically encoded lanthanide-binding tags (LBTs) inserted at the extracellular end of the S4 segment of each domain (with a single LBT per construct)...
March 7, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28202576/differential-effect-of-brief-electrical-stimulation-on-voltage-gated-potassium-channels
#11
Morven Alison Cameron, Amr Al Abed, Yossi Buskila, Socrates Dokos, Nigel H Lovell, John W Morley
Electrical stimulation of neuronal tissue is a promising strategy to treat a variety of neurological disorders. The mechanism of neuronal activation by external electrical stimulation is governed by voltage-gated ion channels. This stimulus, typically brief in nature, leads to membrane potential depolarization, which increases ion flow across the membrane by increasing the open probability of these voltage-gated channels. In spiking neurons, it is activation of voltage-gated sodium channels (NaV-channels) that leads to action potential generation...
February 15, 2017: Journal of Neurophysiology
https://www.readbyqxmd.com/read/28195313/neuronal-sodium-channels-emerging-components-of-the-nano-machinery-of-cardiac-calcium-cycling
#12
Rengasayee Veeraraghavan, Sándor Györke, Przemysław B Radwański
Excitation-contraction coupling (ECC) is the bridge between cardiac electrical activation and mechanical contraction. It is driven by the influx of Ca(2+) across the sarcolemma triggering Ca(2+) release from the sarcoplasmic reticulum (SR) - a process termed Ca(2+) -induced Ca(2+) release (CICR) - followed by re-sequestration of Ca(2+) into the SR. The sodium calcium exchanger (NCX) inextricably couples the cycling of Ca(2+) and Na(+) in cardiac myocytes. Thus, influx of Na(+) via voltage-gated Na(+) channels (NaV ) has emerged as an important regulator of CICR both in health and in disease...
February 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28195065/effect-of-econazole-and-benzydamine-on-sensory-neurons-in-culture
#13
S Mathivanan, R de la Torre-Martinez, C Wolf, G Mangano, L Polenzani, C Milanese, A Ferrer-Montiel
Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, and for the therapy of vaginal candidiasis. Topical application of this azole is generally safe, although some patients have complained of mild burning sensation/cutaneous irritation and itching, especially when administered intravaginally. The underlying mechanisms responsible of these adverse effects are poorly understood, though they suggest excitation of cutaneous nociceptor terminals. We report that exposure of primary cultures of rat nociceptors to econazole augments neuronal excitability...
December 2016: Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society
https://www.readbyqxmd.com/read/28188741/molecular-dynamics-study-of-ion-transport-through-an-open-model-of-voltage-gated-sodium-channel
#14
Yang Li, Ruining Sun, Huihui Liu, Haipeng Gong
Voltage-gated sodium (NaV) channels are critical in the signal transduction of excitable cells. In this work, we modeled the open conformation for the pore domain of a prokaryotic NaV channel (NaVRh), and used molecular dynamics simulations to track the translocation of dozens of Na(+) ions through the channel in the presence of a physiological transmembrane ion concentration gradient and a transmembrane electrical field that was closer to the physiological one than previous studies. Channel conductance was then estimated from simulations on the wide-type and DEKA mutant of NaVRh...
February 8, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28184187/ankyrin-g-membrane-partners-drive-the-establishment-and-maintenance-of-the-axon-initial-segment
#15
Christophe Leterrier, Nadine Clerc, Fanny Rueda-Boroni, Audrey Montersino, Bénédicte Dargent, Francis Castets
The axon initial segment (AIS) is a highly specialized neuronal compartment that plays a key role in neuronal development and excitability. It concentrates multiple membrane proteins such as ion channels and cell adhesion molecules (CAMs) that are recruited to the AIS by the scaffold protein ankyrin G (ankG). The crucial function of ankG in the anchoring of AIS membrane components is well established, but a reciprocal role of membrane partners in ankG targeting and stabilization remained elusive. In rat cultured hippocampal neurons and cortical organotypic slices, we found that shRNA-mediated knockdown of ankG membrane partners (voltage-gated sodium channels (Nav) or neurofascin-186) led to a decrease of ankG concentration and perturbed the AIS formation and maintenance...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28183995/structure-of-a-eukaryotic-voltage-gated-sodium-channel-at-near-atomic-resolution
#16
Huaizong Shen, Qiang Zhou, Xiaojing Pan, Zhangqiang Li, Jianping Wu, Nieng Yan
Voltage-gated sodium (Nav) channels are responsible for the initiation and propagation of action potentials. They are associated with a variety of channelopathies and are targeted by multiple pharmaceutical drugs and natural toxins. Here, we report the cryo-EM structure of a putative Nav channel from American cockroach (designated NavPaS) at 3.8-Å resolution. The voltage sensing domains (VSDs) of the four repeats exhibit distinct conformations. The entrance to the asymmetric selectivity filter vestibule is guarded by heavily glycosylated and disulfide bond-stabilized extracellular loops...
February 9, 2017: Science
https://www.readbyqxmd.com/read/28182562/in-silico-modeling-of-the-functional-role-of-reduced-sialylation-in-sodium-and-potassium-channel-gating-of-mouse-ventricular-myocytes
#17
Dongping Du, Hui Yang, Andrew R Ednie, Eric S Bennett
Cardiac ion channels are highly glycosylated membrane proteins, with up to 30% of the protein's mass containing glycans. Heart diseases often accompany individuals with congenital disorders of glycosylation (CDG). However, cardiac dysfunction among CDG patients is not yet fully understood. There is an urgent need to study how aberrant glycosylation impacts cardiac electrical signaling. Our previous works reported that congenitally reduced sialylation achieved through deletion of the sialyltransferase gene, ST3Gal4, leads to altered gating of voltage-gated Na+ and K+ channels (Nav and Kv, respectively)...
February 6, 2017: IEEE Journal of Biomedical and Health Informatics
https://www.readbyqxmd.com/read/28171721/simulating-the-activation-of-voltage-sensing-domain-for-a-voltage-gated-sodium-channel-using-polarizable-force-field
#18
Rui-Ning Sun, Haipeng Gong
Voltage-gated sodium (NaV) channels play vital roles in the signal transduction of excitable cells. Upon activation of a NaV channel, the change of transmembrane voltage triggers conformational change of the voltage sensing domain, which then elicits opening of the pore domain and thus allows an influx of Na(+) ions. Description of this process with atomistic details is in urgent demand. In this work, we simulated the partial activation process of the voltage sensing domain of a prokaryotic NaV channel using a polarizable force field...
February 9, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28166971/functional-and-molecular-characterization-of-voltage-gated-sodium-channel-nav-1-8-in-bull-spermatozoa
#19
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/28150151/structure-based-assessment-of-disease-related-mutations-in-human-voltage-gated-sodium-channels
#20
REVIEW
Weiyun Huang, Minhao Liu, S Frank Yan, Nieng Yan
Voltage-gated sodium (Nav) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms...
February 1, 2017: Protein & Cell
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