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Toxin channel

Ning Luan, Wang Shen, Jie Liu, Bo Wen, Zhilong Lin, Shilong Yang, Ren Lai, Siqi Liu, Mingqiang Rong
Scorpion venom is deemed to contain many toxic peptides as an important source of natural compounds. Out of the two hundred proteins identified in Mesobuthus martensii (M. martensii), only a few peptide toxins have been found so far. Herein, a combinational approach based upon RNA sequencing and Liquid chromatography-mass spectrometry/mass spectrometry (LC MS/MS) was employed to explore the venom peptides in M. martensii. A total of 153 proteins were identified from the scorpion venom, 26 previously known and 127 newly identified...
October 5, 2016: Toxins
Andrew G Yee, Peter S Freestone, Ji-Zhong Bai, Janusz Lipski
Parkinson's disease (PD) is not only associated with degeneration of dopaminergic (DAergic) neurons in the Substantia Nigra, but also with profound loss of noradrenergic neurons in the Locus Coeruleus (LC). Remarkably, LC degeneration may exceed, or even precede the loss of nigral DAergic neurons, suggesting that LC neurons may be more susceptible to damage by various insults. Using a combination of electrophysiology, fluorescence imaging and electrochemistry, we directly compared the responses of LC, nigral DAergic and nigral non-dopaminergic (non-DAergic) neurons in rat brain slices to acute application of rotenone, a mitochondrial toxin used to create animal and in vitro models of PD...
October 19, 2016: Experimental Neurology
Daryl C Yang, Jennifer R Deuis, Daniel Dashevsky, James Dobson, Timothy N W Jackson, Andreas Brust, Bing Xie, Ivan Koludarov, Jordan Debono, Iwan Hendrikx, Wayne C Hodgson, Peter Josh, Amanda Nouwens, Gregory J Baillie, Timothy J C Bruxner, Paul F Alewood, Kelvin Kok Peng Lim, Nathaniel Frank, Irina Vetter, Bryan G Fry
Millions of years of evolution have fine-tuned the ability of venom peptides to rapidly incapacitate both prey and potential predators. Toxicofera reptiles are characterized by serous-secreting mandibular or maxillary glands with heightened levels of protein expression. These glands are the core anatomical components of the toxicoferan venom system, which exists in myriad points along an evolutionary continuum. Neofunctionalisation of toxins is facilitated by positive selection at functional hotspots on the ancestral protein and venom proteins have undergone dynamic diversification in helodermatid and varanid lizards as well as advanced snakes...
October 18, 2016: Toxins
Emmanuel Bourinet, Gerald W Zamponi
Venoms from various predatory species, such as fish hunting mollusks scorpions, snakes and arachnids contain a large spectrum of toxins that include blockers of voltage-gated calcium channels. These peptide blockers act by two principal manners - physical occlusion of the pore and prevention of activation gating. Many of the calcium channel-blocking peptides have evolved to tightly occupy their binding pocket on the principal pore forming subunit of the channel, often rendering block poorly reversible. Moreover, several of the best characterized blocking peptides have developed a high degree of channel subtype selectivity...
October 15, 2016: Neuropharmacology
F H Matsubara, G O Meissner, V Herzig, H C Justa, B C L Dias, D Trevisan-Silva, L H Gremski, W Gremski, A Senff-Ribeiro, O M Chaim, G F King, S S Veiga
Loxosceles intermedia venom comprises a complex mixture of proteins, glycoproteins and low molecular mass peptides that act synergistically to immobilize envenomed prey. Analysis of a venom-gland transcriptome from L. intermedia revealed that knottins, also known as inhibitor cystine knot peptides, are the most abundant class of toxins expressed in this species. Knottin peptides contain a particular arrangement of intramolecular disulphide bonds, and these peptides typically act upon ion channels or receptors in the insect nervous system, triggering paralysis or other lethal effects...
October 15, 2016: Insect Molecular Biology
David M Housley, Gary D Housley, Michael J Liddell, Ernest A Jennings
This review categorizes functionally validated actions of defined scorpion toxin (SCTX) neuropeptides across ion channel subclasses, highlighting key trends in this rapidly evolving field. Scorpion envenomation is a common event in many tropical and subtropical countries, with neuropharmacological actions, particularly autonomic nervous system modulation, causing significant mortality. The primary active agents within scorpion venoms are a diverse group of small neuropeptides that elicit specific potent actions across a wide range of ion channel classes...
October 8, 2016: Neuropharmacology
Soshi Seike, Masaya Takehara, Keiko Kobayashi, Masahiro Nagahama
BACKGROUND: Beta-toxin produced by Clostridium perfringens is a key virulence factor of fatal hemorrhagic enterocolitis and enterotoxemia. This toxin belongs to a family of β-pore-forming toxins (PFTs). We reported recently that the ATP-gated P2X7 receptor interacts with beta-toxin. The ATP-release channel pannexin 1 (Panx1) is an important contributor to P2X7 receptor signaling. Hence, we investigated the involvement of Panx1 in beta-toxin-caused cell death. METHODS: We examined the effect of Panx1 in beta-toxin-induced cell death utilizing selective antagonists, knockdown of Panx1, and binding using dot-blot analysis...
October 5, 2016: Biochimica et Biophysica Acta
Daxu Li, Rong Chen, Shin-Ho Chung
Tertiapin (TPN), a short peptide isolated from the venom of the honey bee, is a potent and selective blocker of the inward rectifier K(+) (Kir) channel Kir3.2. Here we examine in atomic detail the binding mode of TPN to Kir3.2 using molecular dynamics, and deduce the key residue in Kir3.2 responsible for TPN selectivity. The binding of TPN to Kir3.2 is stable when the side chain of either Lys16 (TPN(K16)-Kir3.2) or Lys17 (TPN(K17)-Kir3.2) of the toxin protrudes into the channel pore. However, the binding affinity calculated from only TPN(K17)-Kir3...
September 30, 2016: Biophysical Chemistry
Caroline M Cremonez, Mohitosh Maiti, Steve Peigneur, Juliana Silva Cassoli, Alexandre A A Dutra, Etienne Waelkens, Eveline Lescrinier, Piet Herdewijn, Maria Elena de Lima, Adriano M C Pimenta, Eliane C Arantes, Jan Tytgat
To date, several families of peptide toxins specifically interacting with ion channels in scorpion venom have been described. One of these families comprise peptide toxins (called KTxs), known to modulate potassium channels. Thus far, 202 KTxs have been reported, belonging to several subfamilies of KTxs (called α, β, γ, κ, δ, and λ-KTxs). Here we report on a previously described orphan toxin from Tityus serrulatus venom, named Ts11. We carried out an in-depth structure-function analysis combining 3D structure elucidation of Ts11 and electrophysiological characterization of the toxin...
September 30, 2016: Toxins
Courtney C Cocilova, Sarah L Milton
Harmful algal blooms are increasing in frequency and extent worldwide and occur nearly annually off the west coast of Florida where they affect both humans and wildlife. The dinoflagellate Karenia brevis is a key organism in Florida red tides that produces a suite of potent neurotoxins collectively referred to as the brevetoxins (PbTx). Brevetoxins bind to and open voltage gated sodium channels (VGSC), increasing cell permeability in excitable cells and depolarizing nerve and muscle tissue. Exposed animals may thus show muscular and neurological symptoms including head bobbing, muscle twitching, paralysis, and coma; large HABs can result in significant morbidity and mortality of marine life, including fish, birds, marine mammals, and sea turtles...
September 28, 2016: Aquatic Toxicology
Zhi-Gang Huang, Hao-Wen Liu, Zhen-Zhen Yan, Sheng Wang, Lu-Yang Wang, Jiu-Ping Ding
Large-conductance Ca(2+)- and voltage- activated potassium (MaxiK or BK) channels are composed of a pore-forming α subunit (Slo) and four types of auxiliary β subunits or just a pore-forming α subunit. Although multiple N-linked glycosylation sites in the extracellular loop of β subunits have been identified, very little is known about how glycosylation influences the structure and function of BK channels. Using a combination of site-directed mutagenesis, western blot and patch-clamp recordings, we demonstrated that three sites in the extracellular loop of β2 subunit are N-glycosylated (N-X-T/S at N88, N96 and N119)...
October 3, 2016: Channels
Bin Wu, Yan Zhu, Jian Shi, Jie Tao, Yonghua Ji
BmP02, a short-chain peptide with 28 residues from the venom of Chinese scorpion Buthus martensi Karsch, has been reported to inhibit the transient outward potassium currents (Ito) in rat ventricular muscle cells. However, it remains unclear whether BmP02 modulates the Kv4.2 channel, one of the main contributors to Ito. The present study investigated the effects of BmP02 on Kv4.2 kinetics and its underlying molecular mechanism. The electrophysiological recordings showed that the inactivation of Kv4.2 expressed in HEK293T cells was significantly delayed by BmP02 in a dose-response manner with EC50 of ~850 nM while the peak current, activation and voltage-dependent inactivation of Kv4...
2016: Toxins
Pradeep Sathyanarayana, Rajat Desikan, K Ganapathy Ayappa, Sandhya S Visweswariah
Pore-forming toxins (PFTs) bind to cell membranes and form nanoscale pores that allow leakage of cellular components, resulting in cell death. The water-soluble, monomeric form of these toxins shows a dramatic conformational change during pore formation, as exemplified by crystal structures of the monomer and functional pore of cytolysin A (ClyA). The solvent-exposed, C-terminal residues of the protein are essential for activity, but the mechanism by which this region regulates pore formation remains unknown...
October 13, 2016: Biochemistry
Steven D Aird, Alejandro Villar Briones, Michael C Roy, Alexander S Mikheyev
While decades of research have focused on snake venom proteins, far less attention has been paid to small organic venom constituents. Using mostly pooled samples, we surveyed 31 venoms (six elapid, six viperid, and 19 crotalid) for spermine, spermidine, putrescine, and cadaverine. Most venoms contained all four polyamines, although some in essentially trace quantities. Spermine is a potentially significant component of many viperid and crotalid venoms (≤0.16% by mass, or 7.9 µmol/g); however, it is almost completely absent from elapid venoms assayed...
2016: Toxins
Houcemeddine Othman, Silke Andrea Wieninger, Mohamed ElAyeb, Michael Nilges, Najet Srairi-Abid
Glioblastoma is the deadliest type of brain cancer. Treatment could target the Matrix metalloproteinase-2 (MMP-2), which is known to be involved in the invasion process of glioblastoma cells. But current available inhibitors are not selective to MMP-2 due to their interaction with the catalytic binding site, which is highly conserved in all MMPs structures. Interestingly, members of the chloride channel blocker scorpion toxins, such as chlorotoxin (ClTx) and AaCTx, inhibit glioblastoma cell invasion and show a promising therapeutic potential...
September 28, 2016: Journal of Biomolecular Structure & Dynamics
Carus H Y Lau, Glenn F King, Mehdi Mobli
Voltage-sensor domains (VSDs) are modular transmembrane domains of voltage-gated ion channels that respond to changes in membrane potential by undergoing conformational changes that are coupled to gating of the ion-conducting pore. Most spider-venom peptides function as gating modifiers by binding to the VSDs of voltage-gated channels and trapping them in a closed or open state. To understand the molecular basis underlying this mode of action, we used nuclear magnetic resonance to delineate the atomic details of the interaction between the VSD of the voltage-gated potassium channel KvAP and the spider-venom peptide VSTx1...
September 28, 2016: Scientific Reports
Shangfei Zhang, Limei Zhu, Jie Yu, Jun Xu, Bin Gao, Changlin Zhou, Shunyi Zhu
Grafting of exogenous bioactive sites or functional motifs onto structurally stable scaffolds to gain new functions represents an important research direction in protein engineering. Some engineered proteins have been developed into therapeutic drugs. MeuNaTxα-3 (abbreviated as MT-3) is a newly characterized scorpion sodium channel toxin-like peptide isolated from the venom of the scorpion Mesobuthus eupeus, which contains a rigid scaffold highly similar to classical scorpion sodium channel toxins and an extension of eight amino acids in its J-loop region...
September 26, 2016: Protein Engineering, Design & Selection: PEDS
Wenda Wu, Hui-Ren Zhou, Steven J Bursian, Jane E Link, James J Pestka
The common foodborne mycotoxin deoxynivalenol (DON, vomitoxin) can negatively impact animal and human health by causing food refusal and vomiting. Gut enteroendocrine cells (EECs) secrete hormones that mediate DON's anorectic and emetic effects. In prior work utilizing a cloned EEC model, our laboratory discovered that DON-induced activation of calcium-sensing receptor (CaSR), a G-coupled protein receptor (GPCR), and transient receptor ankyrin-1 (TRPA1), a transient receptor potential (TRP) channel, drives Ca(2+)-mediated hormone secretion...
September 25, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Rongsheng E Wang, Ying Wang, Yuhan Zhang, Chase Gabrelow, Yong Zhang, Victor Chi, Qiangwei Fu, Xiaozhou Luo, Danling Wang, Sean Joseph, Kristen Johnson, Arnab K Chatterjee, Timothy M Wright, Vân T B Nguyen-Tran, John Teijaro, Argyrios N Theofilopoulos, Peter G Schultz, Feng Wang
A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel "stalk-knob" structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both β-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values)...
October 11, 2016: Proceedings of the National Academy of Sciences of the United States of America
Vaishali Bane, Brid Brosnan, Paul Barnes, Mary Lehane, Ambrose Furey
Tetrodotoxin (TTX) is an emerging toxin in the European marine environment. It has various known structural analogues. It acts as a sodium channel blocker; the ability of each analogue to bind to the sodium channel varies with the particular structure of each analogue. Thus, each analogue will vary in its toxic potential. TTX analogues co-occur in food samples at variable concentrations. An LC-MS method was developed for the identification and quantitation of several analogues of TTX using an LTQ-Orbitrap XL mass spectrometer...
September 2016: Food Additives & Contaminants. Part A, Chemistry, Analysis, Control, Exposure & Risk Assessment
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