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https://www.readbyqxmd.com/read/28645932/a-functional-nav1-7-navab-chimera-with-a-reconstituted-high-affinity-protx-ii-binding-site
#1
Ramkumar Rajamani, Sophie Wu, Iyoncy Rodrigo, Mian Gao, Simon Low, Lisa Megson, David Wensel, Rick Pieschl, Debra Post-Munson, John Watson, David R Langley, Michael Ahlijanian, Linda Bristow, James Herrington
NaV1.7 is genetically implicated in human pain perception. Rare gain of function mutations in NaV1.7 lead to spontaneous pain in humans whereas loss of function mutations result in congenital insensitivity to pain (CIP). Hence, agents that specifically modulate the function of NaV1.7 have the potential to yield novel therapeutics to treat pain. The complexity of the channel and the challenges to generate recombinant cell lines with high NaV1.7 expression have led to a templated target strategy approach employing chimeras with the bacterial channel, NavAb...
June 23, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28629730/synergistic-antinociceptive-effect-of-a-calcium-channel-blocker-and-a-trpv1-blocker-in-an-acute-pain-model-in-mice
#2
Manuella R Palhares, Juliana F Silva, Marcio Junior S Rezende, Duana C Santos, Cláudio A Silva-Junior, Márcia H Borges, Juliano Ferreira, Marcus V Gomez, Célio J Castro Junior
AIMS: Extensive evidence supports a role for voltage-gated calcium channels (VGCC) and TRPV1 receptors in pain transmission and modulation. We investigated the profile of analgesic interaction between Phα1β toxin (a VGCC blocker) and SB366791 (selective TRPV1 antagonist) in a model of acute pain induced by capsaicin. Changes in body temperature induced by combination regimens were also evaluated. MAIN METHODS: Isobolographic approach with a fixed dose-ratio of combined drugs was used to determine whether antinociceptive interaction of Phα1β and SB366791 are subadditive, additive or synergic...
June 16, 2017: Life Sciences
https://www.readbyqxmd.com/read/28611679/icariin-a-novel-blocker-of-sodium-and-calcium-channels-eliminates-early-and-delayed-afterdepolarizations-as-well-as-triggered-activity-in-rabbit-cardiomyocytes
#3
Wanzhen Jiang, Mengliu Zeng, Zhenzhen Cao, Zhipei Liu, Jie Hao, Peipei Zhang, Youjia Tian, Peihua Zhang, Jihua Ma
Icariin, a flavonoid monomer from Herba Epimedii, has confirmed pharmacological and biological effects. However, its effects on arrhythmias and cardiac electrophysiology remain unclear. Here we investigate the effects of icariin on ion currents and action potentials (APs) in the rabbit myocardium. Furthermore, the effects of icariin on aconitine-induced arrhythmias were assessed in whole rabbits. Ion currents and APs were recorded in voltage-clamp and current-clamp mode in rabbit left ventricular myocytes (LVMs) and left atrial myocytes (LAMs), respectively...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28611355/improved-efficacy-of-an-arthropod-toxin-expressing-fungus-against-insecticide-resistant-malaria-vector-mosquitoes
#4
Etienne Bilgo, Brian Lovett, Weiguo Fang, Niraj Bende, Glenn F King, Abdoulaye Diabate, Raymond J St Leger
The continued success of malaria control efforts requires the development, study and implementation of new technologies that circumvent insecticide resistance. We previously demonstrated that fungal pathogens can provide an effective delivery system for mosquitocidal or malariacidal biomolecules. Here we compared genes from arthropod predators encoding insect specific sodium, potassium and calcium channel blockers for their ability to improve the efficacy of Metarhizium against wild-caught, insecticide-resistant anophelines...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28607094/pharmacology-of-the-nav1-1-domain-iv-voltage-sensor-reveals-coupling-between-inactivation-gating-processes
#5
Jeremiah D Osteen, Kevin Sampson, Vivek Iyer, David Julius, Frank Bosmans
The Nav1.1 voltage-gated sodium channel is a critical contributor to excitability in the brain, where pathological loss of function leads to such disorders as epilepsy, Alzheimer's disease, and autism. This voltage-gated sodium (Nav) channel subtype also plays an important role in mechanical pain signaling by primary afferent somatosensory neurons. Therefore, pharmacologic modulation of Nav1.1 represents a potential strategy for treating excitability disorders of the brain and periphery. Inactivation is a complex aspect of Nav channel gating and consists of fast and slow components, each of which may involve a contribution from one or more voltage-sensing domains...
June 12, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28598389/identification-of-a-novel-o-conotoxin-reveals-an-unusual-and-potent-inhibitor-of-the-human-%C3%AE-9%C3%AE-10-nicotinic-acetylcholine-receptor
#6
Shantong Jiang, Han-Shen Tae, Shaoqiong Xu, Xiaoxia Shao, David J Adams, Chunguang Wang
Conotoxins are a pool of disulfide-rich peptide neurotoxins produced by cone snails for predation and defense. They are a rich reservoir of novel ligands for ion channels, neurotransmitter receptors and transporters in the nervous system. In this study, we identified a novel conotoxin component, O-conotoxin GeXXVIIA, from the venom of Conus generalis. The native form of this component is a disulfide-linked homodimer of a 5-Cys-containing peptide. Surprisingly, our electrophysiological studies showed that, in comparison to the folded monomers, the linear peptide of this toxin had the highest inhibitory activity at the human α9α10 nicotinic acetylcholine receptor (nAChR), with an IC50 of 16...
June 9, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28597209/molecular-dynamics-simulation-reveals-unique-interplays-between-a-tarantula-toxin-and-lipid-membranes
#7
Lei Wu, Si-Si Xie, Er Meng, Wen-Ying Li, Long Liu, Dong-Yi Zhang
Tarantula toxins compose an important class of spider toxins that target ion channels, and some are known to interact with lipid membranes. In this study, we focus on a tarantula toxin, Jingzhaotoxin-III (JZTx-III) that specifically targets the cardiac voltage-gated sodium channel Na[Formula: see text]1.5 and is suspected to be able to interact with lipid membranes. Here, we use an all-atom model and long-term molecular dynamics simulations to investigate the interactions between JZTx-III and lipid membranes of different compositions...
June 8, 2017: Journal of Membrane Biology
https://www.readbyqxmd.com/read/28596383/reinvestigation-of-the-biological-activity-of-d-allo-shk-protein
#8
Bobo Dang, Sandeep Chhabra, Michael W Pennington, Raymond S Norton, Stephen B H Kent
ShK toxin from the sea anemone Stichodactyla helianthus is a 35-residue protein that binds to the Kv1.3 ion channel with high affinity. Recently we determined the X-ray structure of ShK toxin by racemic crystallography, in the course of which we discovered that D-ShK has a near-background IC50 value ~50,000 times lower than that of the L-ShK toxin. This lack of activity was at odds with previously reported results for an ShK diastereomer designated D-allo-ShK for which significant biological activity had been observed in a similar receptor-blocking assay...
June 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28591591/activation-of-sodium-channel-by-a-novel-%C3%AE-scorpion-toxin-bmk-nt2-stimulates-erk1-2-and-cerb-phosphorylation-through-a-ca-2-dependent-pathway-in-neocortical-neurons
#9
Xiaohan Zou, Ying Wu, Juan Chen, Fang Zhao, Fan Zhang, Boyang Yu, Zhengyu Cao
Neuronal excitability controls the expression of a variety of genes and proteins and therefore regulates neurite outgrowth and synapse formation, fundamental physiological processes controlling learning and memory. Scorpion venom contains many neurotoxins which alter ion channel activities that influence neuronal excitability. In this study, a novel scorpion peptide termed BmK NT2 was purified from venom of Chinese scorpion Buthus martensii Karsch by combining mass spectrum mapping and intracellular Ca(2+) concentration measurement in primary cultured neocortical neurons...
June 4, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28583325/neuroprotective-effect-of-low-intensity-pulsed-ultrasound-against-mpp-induced-neurotoxicity-in-pc12-cells-involvement-of-k2p-channels-and-stretch-activated-ion-channels
#10
Lu Zhao, Yi Feng, Aiwei Shi, Lei Zhang, Shifang Guo, Mingxi Wan
Parkinson's disease is the second most common neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenylpyridinium (MPP(+)) is a dopaminergic neuronal toxin that is widely used in constructing Parkinson's disease models in vitro. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapeutic approach that has neuromodulation and neuroprotective effects in the central neural system; however, whether LIPUS can provide protection for dopaminergic neurons against MPP(+)-induced neurocytotoxicity remains unknown...
June 2, 2017: Ultrasound in Medicine & Biology
https://www.readbyqxmd.com/read/28582558/promed-mail-22-years-of-digital-surveillance-of-emerging-infectious-diseases
#11
Malwina Carrion, Lawrence C Madoff
ProMED-mail (ProMED) was launched in 1994 as an email service to identify unusual health events related to emerging and re-emerging infectious diseases and toxins affecting humans, animals and plants. It is used daily by public health leaders, government officials at all levels, physicians, veterinarians and other healthcare workers, researchers, private companies, journalists and the general public. Reports are produced and commentary provided by a global team of subject matter experts in a variety of fields including virology, parasitology, epidemiology, entomology, veterinary and plant disease specialists...
May 1, 2017: International Health
https://www.readbyqxmd.com/read/28557348/the-toxic-mode-of-action-of-cyclic-lipodepsipeptide-fusaricidins-produced-by-paenibacillus-polymyxa-toward-mammalian-cells
#12
Raimo Mikkola, Maria A Andersson, Pavel Grigoriev, Mari Heinonen, Mirja S Salkinoja-Salonen
AIMS: The toxic strains of Paenibacillus polymyxa were isolated from buildings connected to ill health symptoms. Our aim was to identify the toxic compounds of Paenibacillus polymyxa and describe their toxic actions. METHODS AND RESULTS: The toxins of Paenibacillus polymyxa were purified and analysed by HPLC and mass spectrometry. Toxic fusaricidins A and B, and LI-F05a with mass ions at m/z 883.7, 897.6, and 897.6, respectively, were found. Cytotoxicity of purified fusaricidins A and B were measured using boar sperm, porcine tubular kidney epithelial and murine fibroblast cells...
May 29, 2017: Journal of Applied Microbiology
https://www.readbyqxmd.com/read/28553340/aerobic-exercise-combined-with-huwentoxin-i-mitigates-chronic-cerebral-ischemia-injury
#13
Hai-Feng Mao, Jun Xie, Jia-Qin Chen, Chang-Fa Tang, Wei Chen, Bo-Cun Zhou, Rui Chen, Hong-Lin Qu, Chu-Zu Wu
Ca(2+) channel blockers have been shown to protect neurons from ischemia, and aerobic exercise has significant protective effects on a variety of chronic diseases. The present study injected huwentoxin-I (HWTX-I), a spider peptide toxin that blocks Ca(2+) channels, into the caudal vein of a chronic cerebral ischemia mouse model, once every 2 days, for a total of 15 injections. During this time, a subgroup of mice was subjected to treadmill exercise for 5 weeks. Results showed amelioration of cortical injury and improved neurological function in mice with chronic cerebral ischemia in the HWTX-I + aerobic exercise group...
April 2017: Neural Regeneration Research
https://www.readbyqxmd.com/read/28550293/stochastic-sensing-of-angiotensin-ii-with-lysenin-channels
#14
Nisha Shrestha, Sheenah L Bryant, Christopher Thomas, Devon Richtsmeier, Xinzhu Pu, Juliette Tinker, Daniel Fologea
The ability of pore-forming proteins to interact with various analytes has found vast applicability in single molecule sensing and characterization. In spite of their abundance in organisms from all kingdoms of life, only a few pore-forming proteins have been successfully reconstituted in artificial membrane systems for sensing purposes. Lysenin, a pore-forming toxin extracted from the earthworm E. fetida, inserts large conductance nanopores in lipid membranes containing sphingomyelin. Here we show that single lysenin channels may function as stochastic nanosensors by allowing the short cationic peptide angiotensin II to be electrophoretically driven through the conducting pathway...
May 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28542706/modulatory-features-of-the-novel-spider-toxin-%C3%AE-trtx-df1a-isolated-from-the-venom-of-the-spider-davus-fasciatus
#15
Fernanda C Cardoso, Zoltan Dekan, Jennifer J Smith, Jennifer R Deuis, Irina Vetter, Volker Herzig, Paul F Alewood, Glenn F King, Richard J Lewis
BACKGROUND AND PURPOSE: Naturally occurring dysfunction in NaV channels results in complex disorders such as chronic pain, making these channels an attractive target for new therapies. In the pursuit of novel NaV modulators, we investigated spider venoms for new inhibitors of NaV channels. EXPERIMENTAL APPROACH: We used high-throughput screens to identify a NaV modulator in venom of the spider Davus fasciatus. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modeling and a rodent pain model...
May 24, 2017: British Journal of Pharmacology
https://www.readbyqxmd.com/read/28538150/lanthanides-report-calcium-sensor-in-the-vestibule-of-ryanodine-receptor
#16
Sándor Sárközi, István Komáromi, István Jóna, János Almássy
Ca(2+) regulates ryanodine receptor's (RyR) activity through an activating and an inhibiting Ca(2+)-binding site located on the cytoplasmic side of the RyR channel. Their altered sensitivity plays an important role in the pathology of malignant hyperthermia and heart failure. We used lanthanide ions (Ln(3+)) as probes to investigate the Ca(2+) sensors of RyR, because they specifically bind to Ca(2+)-binding proteins and they are impermeable to the channel. Eu(3+)'s and Sm(3+)'s action was tested on single RyR1 channels reconstituted into planar lipid bilayers...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28535116/is-mannitol-the-treatment-of-choice-for-patients-with-ciguatera-fish-poisoning
#17
Michael E Mullins, Robert S Hoffman
CONTEXT: Ciguatera fish poisoning arises primarily from consumption of carnivorous reef fish caught in tropical and sub-tropical waters. Ciguatoxins, a class of tasteless, heat-stable, polycyclic toxins produced by dinoflagellates, accumulate through the food chain and concentrate in various carnivorous fish, such as groupers, barracudas, wrasses, amberjack, kingfishes, and eels. Characteristics of ciguatera fish poisoning include early nausea, vomiting, and diarrhea in the first one to two days post ingestion, followed by the appearance of sensory disturbances...
May 23, 2017: Clinical Toxicology
https://www.readbyqxmd.com/read/28528671/voltage-gated-sodium-channel-pharmacology-insights-from-molecular-dynamics-simulations
#18
Rong Chen, Amanda Buyan, Ben Corry
Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and how they can selectively bind to one channel subtype over another...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528669/modulation-of-ion-channels-by-cysteine-rich-peptides-from-sequence-to-structure
#19
Mehdi Mobli, Eivind A B Undheim, Lachlan D Rash
Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical "toxin-to-sequence" approach to venom peptide biodiscovery...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28526576/carvacrol-promotes-neuroprotection-in-the-mouse-hemiparkinsonian-model
#20
L M Dati, H Ulrich, C C Real, Z P Feng, H S Sun, L R Britto
Carvacrol is a monoterpene that has been linked to neuroprotection in several animal models of neurodegeneration, including ischemia, epilepsy and traumatic neuronal injury. In this study, we investigated the effects of carvacrol (i.p.) upon the neurodegeneration induced by 6-hydroxy-dopamine unilateral intrastriatal injections in mice. We have also used the cylinder test to assess the behavioral effects of carvacrol in that model of Parkinson's disease, and immunoblots to evaluate the levels of caspase-3 and TRPM7, one of major targets of carvacrol...
May 17, 2017: Neuroscience
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