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https://www.readbyqxmd.com/read/28428547/the-tarantula-toxin-%C3%AE-%C3%AE-trtx-pre1a-highlights-the-importance-of-the-s1-s2-voltage-sensor-region-for-sodium-channel-subtype-selectivity
#1
Joshua S Wingerd, Christine A Mozar, Christine A Ussing, Swetha S Murali, Yanni K-Y Chin, Ben Cristofori-Armstrong, Thomas Durek, John Gilchrist, Christopher W Vaughan, Frank Bosmans, David J Adams, Richard J Lewis, Paul F Alewood, Mehdi Mobli, Macdonald J Christie, Lachlan D Rash
Voltage-gated sodium (NaV) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal NaV channels inhibiting peak current of hNaV1.1, rNaV1.2, hNaV1.6, and hNaV1.7 while concurrently inhibiting fast inactivation of hNaV1.1 and rNaV1...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28428070/no-production-and-potassium-channels-activation-induced-by-crotalus-durissus-cascavella-underlie-mesenteric-artery-relaxation
#2
S S Santos, R L C Jesus, L O Simões, W P Vasconcelos, I A Medeiros, R C Veras, L L Casais-E-Silva, D F Silva
Animal toxins are natural resources for pharmacological studies. The venom of Crotalus durissus cascavella (C.d. cascavella) may be a source in the bio-prospecting of new anti-hypertensive agents. The aim of this study was to investigate vascular effects of the venom of C.d. cascavella in normotensive rats. Studies were performed using isolated mesenteric artery segments and aortic endothelial cells. The cumulative administration of the venom of C.d. cascavella (0.001-30 μg/mL) on phenylephrine (Phe; 10 μM) pre-contracted rings induced a concentration-dependent vasorelaxation in the presence of vascular endothelium (Emax = 47...
April 18, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28426823/observation-of-%C3%AF-pore-currents-in-mutant-hkv1-2_v370c-potassium-channels
#3
Pavel Tyutyaev, Stephan Grissmer
Current through the σ-pore was first detected in hKv1.3_V388C channels, where the V388C mutation in hKv1.3 channels opened a new pathway (σ-pore) behind the central α-pore. Typical for this mutant channel was inward current at potentials more negative than -100 mV when the central α-pore was closed. The α-pore blockers such as TEA+ and peptide toxins (CTX, MTX) could not reduce current through the σ-pore of hKv1.3_V388C channels. This new pathway would proceed in parallel to the α-pore in the S6-S6 interface gap...
2017: PloS One
https://www.readbyqxmd.com/read/28416444/the-pharmacology-of-voltage-gated-sodium-channel-activators
#4
REVIEW
Jennifer R Deuis, Alexander Mueller, Mathilde R Israel, Irina Vetter
Toxins and venom components that target voltage-gated sodium (NaV) channels have evolved numerous times due to the importance of this class of ion channels in the normal physiological function of peripheral and central neurons as well as cardiac and skeletal muscle. NaV channel activators in particular have been isolated from the venom of spiders, wasps, snakes, scorpions, cone snails and sea anemone and are also produced by plants, bacteria and algae. These compounds have provided key insight into the molecular structure, function and pathophysiological roles of NaV channels and are important tools due to their at times exquisite subtype-selectivity...
April 14, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28415833/molecular-characterization-and-biodiversity-of-a-putative-chlorotoxin-from-the-iranian-yellow-scorpion-odontobuthus-doriae
#5
Maryam Naderi Soorki, Amir Jalali, Hamid Galehdari
BAckground: Chloride channels have already been over-expressed in the different types of cancer. Chlorotoxins, as the blocking agent of these channels, have been indicated to be an effective drug against tumors. In this study, we characterized a putative chlorotoxin from a cDNA library of the venom glands obtained from the Iranian scorpion Odontobuthus doriae. Methods: A cDNA library was constructed from venom gland transcriptome of six scorpions. The cDNA encoding Odontobuthus doriae chlorotoxin was isolated from the library, and its putative peptide was characterized by some bioinformatics software such as protein blast, SignalP4...
April 18, 2017: Iranian Biomedical Journal
https://www.readbyqxmd.com/read/28410268/long-term-anti-itch-effect-of-botulinum-neurotoxin-a-is-associated-with-downregulation-of-trpv1-and-trpa1-in-the-dorsal-root-ganglia-in-mice
#6
Lei-Fang Cao, Meng Si, Ya Huang, Li-Hua Chen, Xiao-Yan Peng, Ya-Qin Qin, Teng-Teng Liu, Yan Zhou, Tong Liu, Wei-Feng Luo
Itch is a common symptom in patients with skin and systemic diseases, but the effective treatment is limited. Here, we evaluated the anti-itch effects of the botulinum toxin type A (BoNT/A) using acute and chronic dry skin itch mouse models, which were induced by compound 48/80, chloroquine, and a mixture of acetone-diethylether-water treatment, respectively. Pretreatment of intradermal BoNT/A exerted long-term inhibitory effects on compound 48/80-induced and chloroquine-induced acute itch on days 1, 3, 7, and 14, but not on day 21, in mice...
April 13, 2017: Neuroreport
https://www.readbyqxmd.com/read/28400471/a-novel-tarantula-toxin-stabilizes-the-deactivated-voltage-sensor-of-bacterial-sodium-channel
#7
Cheng Tang, Xi Zhou, Phuong Tran Nguyen, Yunxiao Zhang, Zhaotun Hu, Changxin Zhang, Vladimir Yarov-Yarovoy, Paul G DeCaen, Songping Liang, Zhonghua Liu
Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. The crystal structures of several bacterial NaVs have captured the voltage sensor module (VSM) in an activated state, but structure of the deactivated voltage sensor remains elusive. In this study, we sought to identify peptide toxins stabilizing the deactivated VSM of bacterial NaVs. We screened fractions from several venoms and characterized a cystine knot toxin called JZTx-27 from the venom of tarantula Chilobrachys jingzhao as a high-affinity antagonist of the prokaryotic NaVs nonselective voltage-gated, Bacillus alcalophilus (NsVBa) and bacterial sodium channel from Bacillus halodurans(NaChBac) (IC50 = 112 nM and 30 nM, respectively)...
April 11, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28400258/gating-modifier-toxin-interactions-with-ion-channels-and-lipid-bilayers-is-the-trimolecular-complex-real
#8
REVIEW
Akello J Agwa, Sónia T Henriques, Christina I Schroeder
Spider peptide toxins have attracted attention because of their ability to target voltage-gated ion channels, which are involved in several pathologies including chronic pain and some cardiovascular conditions. A class of these peptides acts by modulating the gating mechanism of voltage-gated ion channels and are thus called gating modifier toxins (GMTs). In addition to their interactions with voltage-gated ion channels, some GMTs have affinity for lipid bilayers. This review discusses the potential importance of the cell membrane on the mode of action of GMTs...
April 8, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28398099/enhancing-the-therapeutic-potential-of-peptide-toxins
#9
Raymond S Norton
Peptide toxins are potent and often exquisitely selective probes of the structure and function of ion channels and receptors, and as such are of significant interest to the pharmaceutical and biotech industries as both therapeutic leads and pharmacological tools. Their progression as clinical candidates, however, faces many of the challenges that are common to peptide drugs generally. Areas covered: The attributes of peptide toxins as therapeutic leads are outlined, as well as some of the limiting factors that have hampered the clinical development of many promising candidates...
April 20, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28396446/identification-of-a-cono-rfamide-from-the-venom-of-conus-textile-that-targets-asic3-and-enhances-muscle-pain
#10
Catharina Reimers, Cheng-Han Lee, Hubert Kalbacher, Yuemin Tian, Chih-Hsien Hung, Axel Schmidt, Lea Prokop, Silke Kauferstein, Dietrich Mebs, Chih-Cheng Chen, Stefan Gründer
Acid-sensing ion channels (ASICs) are proton-gated Na(+) channels that are expressed throughout the nervous system. ASICs have been implicated in several neuronal disorders, like ischemic stroke, neuronal inflammation, and pathological pain. Several toxins from venomous animals have been identified that target ASICs with high specificity and potency. These toxins are extremely useful in providing protein pharmacophores and to characterize function and structure of ASICs. Marine cone snails contain a high diversity of toxins in their venom such as conotoxins, which are short polypeptides stabilized by disulfide bonds, and conopeptides, which have no or only one disulfide bond...
April 10, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28363794/adaptive-evolution-of-insect-selective-excitatory-%C3%AE-type-sodium-channel-neurotoxins-from-scorpion-venom
#11
Wenlan Wu, Zhongjie Li, Yibao Ma
Insect selective excitatory β-type sodium channel neurotoxins from scorpion venom (β-NaScTxs) are composed of about 70-76 amino acid residues and share a common scaffold stabilized by four unique disulfide bonds. The phylogenetic analysis of these toxins was hindered by limited sequence data. In our recent study, two new insect selective excitatory β-NaScTxs, LmIT and ImIT, were isolated from Lychas mucronatus and Isometrus maculatus, respectively. With the sequences previously reported, we examined the adaptive molecular evolution of insect selective excitatory β-NaScTxs by estimating the nonsynonymous-to-synonymous rate ratio (ω=dN/dS)...
March 28, 2017: Peptides
https://www.readbyqxmd.com/read/28326549/the-three-finger-toxin-fold-a-multifunctional-structural-scaffold-able-to-modulate-cholinergic-functions
#12
REVIEW
Pascal Kessler, Pascale Marchot, Marcela Silva, Denis Servent
Three-finger fold toxins are miniproteins frequently found in Elapidae snake venoms. This fold is characterized by three distinct loops rich in β-strands and emerging from a dense, globular core reticulated by four highly conserved disulfide bridges. The number and diversity of receptors, channels, and enzymes identified as targets of three-finger fold toxins is increasing continuously. Such manifold diversity highlights the specific adaptability of this fold for generating pleiotropic functions. Although this toxin superfamily disturbs many biological functions by interacting with a large diversity of molecular targets, the most significant target is the cholinergic system...
March 21, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28320963/conformational-dynamics-and-role-of-the-acidic-pocket-in-asic-ph-dependent-gating
#13
Sabrina Vullo, Gaetano Bonifacio, Sophie Roy, Niklaus Johner, Simon Bernèche, Stephan Kellenberger
Acid-sensing ion channels (ASICs) are proton-activated Na(+) channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization...
April 4, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28316260/animal-physiology-and-genetic-aspects-of-ryegrass-staggers-in-grazing-sheep
#14
C A Morris, T T Wheeler, H V Henderson, N R Towers, S H Phua
Ryegrass staggers (RGS) is a metabolic disease of herbivores, caused by the ingestion of perennial ryegrass (Lolium perenne L.) containing a fungal endophyte (Neotyphodium lolii) which produces a tremorgenic toxin, lolitrem B. RGS has a major economic impact for agriculture in New Zealand as well as internationally. Management of RGS in grazing sheep can be problematic, and there is an incomplete knowledge of the interaction between the toxin and the grazing animal. This review is focused on recent advances in understanding the molecular physiology of RGS in the affected animal as well as the influence of animal genetics on the degree of susceptibility to RGS...
March 19, 2017: New Zealand Veterinary Journal
https://www.readbyqxmd.com/read/28301520/the-structure-dynamics-and-selectivity-profile-of-a-nav1-7-potency-optimised-huwentoxin-iv-variant
#15
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/28300784/the-molecular-basis-of-toxins-interactions-with-intracellular-signaling-via-discrete-portals
#16
REVIEW
Adi Lahiani, Ephraim Yavin, Philip Lazarovici
An understanding of the molecular mechanisms by which microbial, plant or animal-secreted toxins exert their action provides the most important element for assessment of human health risks and opens new insights into therapies addressing a plethora of pathologies, ranging from neurological disorders to cancer, using toxinomimetic agents. Recently, molecular and cellular biology dissecting tools have provided a wealth of information on the action of these diverse toxins, yet, an integrated framework to explain their selective toxicity is still lacking...
March 16, 2017: Toxins
https://www.readbyqxmd.com/read/28300777/functional-contributions-of-positive-charges-in-the-pore-lining-helix-3-of-the-bordetella-pertussis-cyaa-hemolysin-to-hemolytic-activity-and-ion-channel-opening
#17
Chattip Kurehong, Chalermpol Kanchanawarin, Busaba Powthongchin, Panchika Prangkio, Gerd Katzenmeier, Chanan Angsuthanasombat
The Bordetella pertussis CyaA-hemolysin (CyaA-Hly) domain was previously demonstrated to be an important determinant for hemolysis against target erythrocytes and ion-channel formation in planar lipid bilayers (PLBs). Here, net-charge variations in the pore-lining helix of thirteen related RTX cytolysins including CyaA-Hly were revealed by amino acid sequence alignments, reflecting their different degrees of hemolytic activity. To analyze possible functional effects of net-charge alterations on hemolytic activity and channel formation of CyaA-Hly, specific mutations were made at Gln(574) or Glu(581) in its pore-lining α3 of which both residues are highly conserved Lys in the three highly active RTX cytolysins (i...
March 16, 2017: Toxins
https://www.readbyqxmd.com/read/28300672/discovery-of-three-toxin-peptides-with-kv1-3-channel-and-il-2-cytokine-inhibiting-activities-from-non-buthidae-scorpions-chaerilus-tricostatus-and-chaerilus-tryznai
#18
Li Ding, Jing Chen, Jinbo Hao, Jiahui Zhang, Xuejun Huang, Fangfang Hu, Zheng Wu, Yaru Liu, Wenxin Li, Zhijian Cao, Yingliang Wu, Jian Li, Shan Li, Hongyan Liu, Wenlong Wu, Zongyun Chen
Non-Buthidae venomous scorpions are huge natural sources of toxin peptides; however, only a few studies have been done to understand their toxin peptides. Herein, we describe three new potential immunomodulating toxin peptides, Ctri18, Ctry68 and Ctry2908, from two non-Buthidae scorpions, Chaerilus tricostatus and Chaerilus tryznai. Sequence alignment analyses showed that Ctri18, Ctry68 and Ctry2908 are three new members of the scorpion toxin α-KTx15 subfamily. Electrophysiological experiments showed that Ctri18, Ctry68 and Ctry2908 blocked the Kv1...
March 12, 2017: Peptides
https://www.readbyqxmd.com/read/28298531/reply-to-yamini-and-nestorovich-alternate-clamped-states-of-the-anthrax-toxin-protective-antigen-channel
#19
Bryan A Krantz
No abstract text is available yet for this article.
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28268294/spatial-characterization-of-innervation-zones-under-electrically-elicited-m-wave
#20
C Zhang, Y Peng, S Li, P Zhou, A Munoz, D Tang, Y Zhang
The three dimensional (3D) innervation zone (IZ) imaging approach (3DIZI) has been developed in our group to localize the IZ of a particular motor unit (MU) from its motor unit action potentials decomposed from high-density surface electromyography (EMG) recordings. In this study, the developed 3DIZI approach was combined with electrical stimulation to investigate global distributions of IZs in muscles from electrically elicited M-wave recordings. Electrical stimulations were applied to the musculocutaneous nerve to activate supramaximal muscle response of the biceps brachii in one healthy subject, and high-density (128 channels) surface EMG signals of the biceps brachii muscles were recorded...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
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