DOCSLIB.ORG

Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey The Journal of Neuroscience, August 1, 2001, 21(15):5594–5500 Vulnerability of 125I-␣-Conotoxin MII Binding Sites to Nigrostriatal Damage in Monkey Maryka Quik,1 Yelena Polonskaya,1 Jennifer M. Kulak,1 and J. Michael McIntosh2 1The Parkinson’s Institute, Sunnyvale, California 94089, and 2Department of Biology and Psychiatry, University of Utah, Salt Lake City, Utah 84112 Parkinson’s disease, a neurodegenerative movement disorder age to the nigrostriatal system and parkinsonism. Autoradio- characterized by selective degeneration of nigrostriatal dopa- graphic analysis showed that 125I-␣-CtxMII sites were selec- minergic neurons, affects ϳ1% of the population over 50. Be- tively reduced (Ն99%) in the basal ganglia and that the lesion- cause nicotinic acetylcholine receptors (nAChRs) may repre- induced decreases correlated well with declines in the sent an important therapeutic target for this disorder, we dopamine transporter, a marker of dopaminergic neuron integ- performed experiments to elucidate the subtypes altered with rity. These findings may indicate that most or all of 125I-␣- nigrostriatal damage in parkinsonian monkeys. For this purpose CtxMII-labeled nAChR subtypes in the basal ganglia are we used 125I-␣-conotoxin MII (CtxMII), a relatively new ligand present on nigrostriatal dopaminergic neurons, in contrast to that identifies ␣3 and/or ␣6 subunits containing nAChR sub- 125I-epibatidine sites. These data suggest that the development types. In brain from untreated monkeys, there was saturable of ligands directed to nAChR subtypes containing ␣3 and/or ␣6 125I-␣-CtxMII binding to a single population of high-affinity subunits may yield a novel treatment strategy for parkinsonian ϭ nicotinic sites (Kd 0.9 nM), primarily localized in the visual, patients with nigrostriatal dopaminergic degeneration. habenula-interpeduncular, and nigrostriatal–mesolimbic path- Key words: ␣-conotoxin MII; ␣3 nAChRs; ␣6 nAChRs; MPTP; ways. Administration of the selective dopaminergic neurotoxin monkeys; autoradiography; nigrostriatal system; dopamine; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine resulted in dam- Parkinson’s disease Accumulating evidence indicates that neuronal nicotine acetyl- disease (Morens et al., 1995; Balfour and Fagerstrom, 1996; choline receptors (nAChRs) may be important in Parkinson’s Gorell et al., 1999), with the risk of developing Parkinson’s disease, a movement disorder characterized by degeneration of disease reduced from 20 to 80% in tobacco users. the nigrostriatal dopaminergic system (Balfour and Fagerstrom, Studies to investigate the nAChR subtypes that mediate the 1996; Quik and Jeyarasasingam, 2000). Nicotinic receptors are effects of nicotine are important because these receptors repre- present in the basal ganglia (Marks and Collins, 1982; Schwartz et sent potential targets for Parkinson’s disease therapy to amelio- al., 1982, 1984; Clarke et al., 1985; Perry et al., 1987, 1995; Aubert rate motor symptoms and/or protect against neurodegeneration. et al., 1992; Marks et al., 1992, 1996; Gotti et al., 1997; Court et nAChRs form a large family of ligand-gated cation channels with al. 2000), and nAChR stimulation evokes striatal dopamine (DA) diverse structures and properties (Changeux et al., 1998; Jones et release (Grady et al., 1992; Marshall et al., 1997; Wonnacott, al., 1999; Lukas et al., 1999; Picciotto et al., 2000). Subunit 1997). Moreover, nicotine and nAChR ligands modulate motor mRNAs present in basal ganglia include ␣2to␣7 and ␤2to␤4 control in rodents, monkeys, and humans (Ishikawa and (Gotti et al., 1997; Wonnacott, 1997; Quik et al., 2000a,b). There Miyatake, 1993; Fagerstrom et al., 1994; Schneider et al., 1998; is thus the potential for receptors with multiple subunit combi- Domino et al., 1999; Kelton et al., 2000), possibly through acti- nations. However, our knowledge of the subtypes expressed in the ␣ ␣ vation of 4 and/or 6 containing nAChRs (Sorenson et al., 1998; basal ganglia has been limited in part by the small number of Arroyo-Jiminez et al., 1999; Le Novere et al., 1999; Ross et al., subtype-selective nAChR radioligands. The use of tritiated nico- 2000). tine and cytisine provides some selectivity for ␣4- and ␤2- Not only does nicotinic receptor stimulation modulate locomo- containing receptors, whereas 125I-␣-bungarotoxin and 3H- tor activity, but nicotine has also been reported to exert a neu- methyllycaconitine selectively bind ␣7-containing receptors roprotective role against dopaminergic damage both in culture (Gotti et al., 1997; Lukas et al., 1999; Whiteaker et al., 1999). and in vivo (Janson et al., 1988; Carr and Rowell, 1990; Belluardo However, radiolabeled epibatidine is relatively nonselective for et al., 1998; Maggio et al., 1998; Quik and Jeyarasasingam, 2000). different nicotinic receptor subtypes and may bind to receptors Moreover, over 50 epidemiological studies indicate that there is containing ␣2 through ␣6 subunits (Perry et al., 1995; Davila- an inverse relationship between tobacco use and Parkinson’s Garcia et al., 1997). 125I-␣-conotoxin MII (CtxMII) is a relatively new ligand that Received Feb. 6, 2001; revised April 30, 2001; accepted May 8, 2001. appears to be selective for receptors containing ␣3 and/or ␣6 This work was supported by the California Tobacco Related Disease Research Program Grant TRDRP 7RT-015 (M.Q.), National Institute on Drug Abuse Grant subunits (Cartier et al., 1996; Kulak et al., 1997; Luo et al., 1998; DA12242 (J.M.M.), National Institute of Mental Health Grant MH53631 (J.M.M.), McIntosh et al., 1999; Vailati et al., 1999; Kuryatov et al., 2000; and National Institute of General Medical Sciences Grant GM48677 (J.M.M.). Whiteaker et al., 2000a). Because this represents a valuable new Correspondence should be addressed to Dr. Maryka Quik, The Parkinson’s Institute, 1170 Morse Avenue, Sunnyvale, CA 94089. E-mail: mquik@parkinsonsinstitute.org. tool to define a subset of nicotinic receptors, we initiated exper- Copyright © 2001 Society for Neuroscience 0270-6474/01/215494-07$15.00/0 iments with 125I-␣-CtxMII in normal and 1-methyl-4-phenyl- Quik et al. • 125I-␣-CtxMII Sites after Nigrostriatal Damage J. Neurosci., August 1, 2001, 21(15):5594–5500 5495 1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkey brain. [125I]RTI-121 autoradiography. 3␤-(4-[ 125I]iodophenyl)tropane-2␤- 125 Monkeys were selected for study because the neuroanatomical carboxylic acid isopropyl ester ([ I]RTI-121; 2200 Ci/mmol; NEN, Boston, MA) was used to identify DA transporters (Quik et al., 2000c). organization of both the basal ganglia and the nAChR subunit Thawed sections were preincubated in buffer containing (in mM): 50 mRNA distribution closely resemble that of humans. Moreover, Tris-HCl, pH 7.4, 120 NaCl, and 5 KCl two times for 15 min at RT. This monkeys treated with the neurotoxin MPTP exhibit behavioral, was followed bya2hrincubation in the same buffer, also containing 125 pathological, and neurochemical changes similar to those ob- 0.025% BSA, 1 ␮M fluoxetine, and 50 pM [ I]RTI-121. The sections served in Parkinson’s disease (Langston et al., 2000; Quik et al., were washed four times for 15 min at 4°C in preincubation buffer, dipped in ice-cold water, air-dried, and placed against Hyperfilm ␤-film for 1–3 2000a,b,c). d with 125I-microscale standards. The uptake inhibitor nomifensine (100 ␮M) was used to define nonspecific binding. There was no binding of the MATERIALS AND METHODS radiolabel to the tissue sections in the presence of nomifensin, with blank binding being identical to the film background. Animals. Twenty young adult male and female squirrel monkeys (Saimiri Quantitation and data analysis. The squirrel monkey (Saimiri sciureus) sciureus) weighing from 0.595 to 0.752 kg were obtained from Osage atlas of Emmers and Akert (1963) was used for identification of the Research Primates (Osage Beach, MO). All animals were housed in a different brain regions. Nissl-stained sections were used to identify brain 13/11 hr light/dark cycle with ad libitum access to food and water. After areas. The area delineating the appropriate regions was quantitated using quarantine and testing according to standard veterinary practice, the computer-assisted densitometry (ImageQuant; Molecular Dynamics, animals were randomly assigned to the control or MPTP treatment Sunnyvale, CA) under standardized light and power conditions. Optical groups. All procedures used in this study conform to the National densities of the film images were determined by subtracting background Institutes of Health (NIH) Guide for the Care and Use of Laboratory from tissue values. The optical density values were converted to femto- Animals and were approved by the Institutional Animal Care and Use moles per milligram of tissue by interpolation from standard curves that Committee. were generated from 125I standards exposed with the tissue sections. The Behavioral testing and MPTP treatment. Quantitative activity assess- sample optical density readings for both the receptor and transporter ment was performed using a computerized movement monitor cage data were within the dynamic (linear) range of the film. The saturation containing an array of infrared sensors (Quik et al., 2000b). After an and competition data represent the results of three or four experiments, initial acclimatization period, the locomotor activity of the monkeys was using one or two tissue sections per experiment for each concentration of monitored fora1hrperiodfor8–12consecutive days, at the same time radiolabeled 125I-␣-CtxMII (saturation) or competing ligand. In all other daily. Then, the animals were assigned randomly to treatment with experiments, the value for the receptor binding for any brain region per MPTP (2 mg/kg, s.c.) or saline. Two to 3 weeks later, locomotor activity monkey was obtained by taking the average value from two to four was measured again as described above, and animals were rated by two independent experiments, with one or two consecutive tissue sections raters, one of whom was blinded, for motor deficits using a parkinsonian used in each experiment. All values are expressed as the mean Ϯ SEM rating scale for nonhuman primates (Langston et al., 2000). The disabil- of the indicated number of animals.
Load more

Recommended publications
  • Interactions of Insecticidal Spider Peptide Neurotoxins with Insect Voltage- and Neurotransmitter-Gated Ion Channels
    Interactions of insecticidal spider peptide neurotoxins with insect voltage- and neurotransmitter-gated ion channels (Molecular representation of - HXTX-Hv1c including key binding residues, adapted from Gunning et al, 2008) PhD Thesis Monique J. Windley UTS 2012 CERTIFICATE OF AUTHORSHIP/ORIGINALITY I certify that the work in this thesis has not previously been submitted for a degree nor has it been submitted as part of requirements for a degree except as fully acknowledged within the text. I also certify that the thesis has been written by me. Any help that I have received in my research work and the preparation of the thesis itself has been acknowledged. In addition, I certify that all information sources and literature used are indicated in the thesis. Monique J. Windley 2012 ii ACKNOWLEDGEMENTS There are many people who I would like to thank for contributions made towards the completion of this thesis. Firstly, I would like to thank my supervisor Prof. Graham Nicholson for his guidance and persistence throughout this project. I would like to acknowledge his invaluable advice, encouragement and his neverending determination to find a solution to any problem. He has been a valuable mentor and has contributed immensely to the success of this project. Next I would like to thank everyone at UTS who assisted in the advancement of this research. Firstly, I would like to acknowledge Phil Laurance for his assistance in the repair and modification of laboratory equipment. To all the laboratory and technical staff, particulary Harry Simpson and Stan Yiu for the restoration and sourcing of equipment - thankyou. I would like to thank Dr Mike Johnson for his continual assistance, advice and cheerful disposition.
    [Show full text]
  • Slow Inactivation in Voltage Gated Potassium Channels Is Insensitive to the Binding of Pore Occluding Peptide Toxins
    Biophysical Journal Volume 89 August 2005 1009–1019 1009 Slow Inactivation in Voltage Gated Potassium Channels Is Insensitive to the Binding of Pore Occluding Peptide Toxins Carolina Oliva, Vivian Gonza´lez, and David Naranjo Centro de Neurociencias de Valparaı´so, Facultad de Ciencias, Universidad de Valparaı´so, Valparaı´so, Chile ABSTRACT Voltage gated potassium channels open and inactivate in response to changes of the voltage across the membrane. After removal of the fast N-type inactivation, voltage gated Shaker K-channels (Shaker-IR) are still able to inactivate through a poorly understood closure of the ion conduction pore. This, usually slower, inactivation shares with binding of pore occluding peptide toxin two important features: i), both are sensitive to the occupancy of the pore by permeant ions or tetraethylammonium, and ii), both are critically affected by point mutations in the external vestibule. Thus, mutual interference between these two processes is expected. To explore the extent of the conformational change involved in Shaker slow inactivation, we estimated the energetic impact of such interference. We used kÿconotoxin-PVIIA (kÿPVIIA) and charybdotoxin (CTX) peptides that occlude the pore of Shaker K-channels with a simple 1:1 stoichiometry and with kinetics 100-fold faster than that of slow inactivation. Because inactivation appears functionally different between outside-out patches and whole oocytes, we also compared the toxin effect on inactivation with these two techniques. Surprisingly, the rate of macroscopic inactivation and the rate of recovery, regardless of the technique used, were toxin insensitive. We also found that the fraction of inactivated channels at equilibrium remained unchanged at saturating kÿPVIIA.
    [Show full text]
  • Conotoxins That Could Provide Analgesia Through Voltage Gated Sodium Channel Inhibition
    Review Conotoxins That Could Provide Analgesia through Voltage Gated Sodium Channel Inhibition Nehan R. Munasinghe and MacDonald J. Christie * Received: 14 August 2015; Accepted: 19 November 2015; Published: 10 December 2015 Academic Editor: Luis Botana Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia; nmun5523@uni.sydney.edu.au * Correspondence: mac.christie@sydney.edu.au; Tel.: +61-2-9351-2946; Fax: +61-2-9351-3868 Abstract: Chronic pain creates a large socio-economic burden around the world. It is physically and mentally debilitating, and many suffers are unresponsive to current therapeutics. Many drugs that provide pain relief have adverse side effects and addiction liabilities. Therefore, a great need has risen for alternative treatment strategies. One rich source of potential analgesic compounds that has immerged over the past few decades are conotoxins. These toxins are extremely diverse and display selective activity at ion channels. Voltage gated sodium (NaV) channels are one such group of ion channels that play a significant role in multiple pain pathways. This review will explore the literature around conotoxins that bind NaV channels and determine their analgesic potential. Keywords: conotoxins; toxins; NaV; ion channels; pain; analgesia; inhibition 1. Introduction Chronic pain is a major problem in the world today. The total cost of chronic pain in the United States was estimated to be between $560 and $635 billion per annum [1]. This cost is greater than cancer and heart diseases combined [1]. The current therapeutics that are available for chronic pain often provide only limited pain relief and have many side effects. Therefore, there is a great need for alternative therapies that provide analgesia to chronic pain sufferers.
    [Show full text]
  • NIH Public Access Author Manuscript Eur J Pharmacol
    NIH Public Access Author Manuscript Eur J Pharmacol. Author manuscript; available in PMC 2012 November 1. NIH-PA Author ManuscriptPublished NIH-PA Author Manuscript in final edited NIH-PA Author Manuscript form as: Eur J Pharmacol. 2011 November 1; 669(1-3): 71±75. doi:10.1016/j.ejphar.2011.08.001. Brain regions mediating α3β4 nicotinic antagonist effects of 18- MC on nicotine self-administration Stanley D. Glick, Elizabeth M. Sell, Sarah E McCallum, and Isabelle M. Maisonneuve Center for Neuropharmacology and Neuroscience, Albany Medical College (MC-136), 47 New Scotland Avenue, Albany, NY 12208, USA Abstract 18-methoxycoronaridine (18-MC), a putative anti-addictive agent, has been shown to decrease the self-administration of several drugs of abuse in rats. 18-MC is a potent antagonist at α3β4 nicotinic receptors. Consistent with high densities of α3β4 nicotinic receptors being located in the medial habenula and the interpeduncular nucleus, 18-MC has been shown to act in these regions to decrease both morphine and methamphetamine self-administration. The present study was conducted to determine if 18-MC’s effect on nicotine self-administration is mediated by acting in these same brain regions. Because moderate densities of α3β4 receptors occur in the dorsolateral tegmentum, ventral tegmental area, and basolateral amygdala, these brain areas were also examined as potential sites of action of 18-MC. Local administration of 18-MC into either the medial habenula, the basolateral amygdala or the dorsolateral tegmentum decreased nicotine self- administration. Surprisingly, local administration of 18-MC into the interpeduncular nucleus increased nicotine self-administration while local administration of 18-MC into the ventral tegmental area had no effect on nicotine self-administration.
    [Show full text]
  • Drug and Medication Classification Schedule
    KENTUCKY HORSE RACING COMMISSION UNIFORM DRUG, MEDICATION, AND SUBSTANCE CLASSIFICATION SCHEDULE KHRC 8-020-1 (11/2018) Class A drugs, medications, and substances are those (1) that have the highest potential to influence performance in the equine athlete, regardless of their approval by the United States Food and Drug Administration, or (2) that lack approval by the United States Food and Drug Administration but have pharmacologic effects similar to certain Class B drugs, medications, or substances that are approved by the United States Food and Drug Administration. Acecarbromal Bolasterone Cimaterol Divalproex Fluanisone Acetophenazine Boldione Citalopram Dixyrazine Fludiazepam Adinazolam Brimondine Cllibucaine Donepezil Flunitrazepam Alcuronium Bromazepam Clobazam Dopamine Fluopromazine Alfentanil Bromfenac Clocapramine Doxacurium Fluoresone Almotriptan Bromisovalum Clomethiazole Doxapram Fluoxetine Alphaprodine Bromocriptine Clomipramine Doxazosin Flupenthixol Alpidem Bromperidol Clonazepam Doxefazepam Flupirtine Alprazolam Brotizolam Clorazepate Doxepin Flurazepam Alprenolol Bufexamac Clormecaine Droperidol Fluspirilene Althesin Bupivacaine Clostebol Duloxetine Flutoprazepam Aminorex Buprenorphine Clothiapine Eletriptan Fluvoxamine Amisulpride Buspirone Clotiazepam Enalapril Formebolone Amitriptyline Bupropion Cloxazolam Enciprazine Fosinopril Amobarbital Butabartital Clozapine Endorphins Furzabol Amoxapine Butacaine Cobratoxin Enkephalins Galantamine Amperozide Butalbital Cocaine Ephedrine Gallamine Amphetamine Butanilicaine Codeine
    [Show full text]
  • Characterisation of a Novel A-Superfamily Conotoxin
    biomedicines Article Characterisation of a Novel A-Superfamily Conotoxin David T. Wilson 1, Paramjit S. Bansal 1, David A. Carter 2, Irina Vetter 2,3, Annette Nicke 4, Sébastien Dutertre 5 and Norelle L. Daly 1,* 1 Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, QLD 4878, Australia; david.wilson4@jcu.edu.au (D.T.W.); paramjit.bansal@jcu.edu.au (P.S.B.) 2 Centre for Pain Research, Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia; d.carter@imb.uq.edu.au (D.A.C.); i.vetter@imb.uq.edu.au (I.V.) 3 School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia 4 Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, LMU Munich, Nußbaumstraße 26, 80336 Munich, Germany; annette.nicke@lrz.uni-muenchen.de 5 Institut des Biomolécules Max Mousseron, UMR 5247, Université de Montpellier, CNRS, 34095 Montpellier, France; sebastien.dutertre@umontpellier.fr * Correspondence: norelle.daly@jcu.edu.au; Tel.: +61-7-4232-1815 Received: 3 May 2020; Accepted: 18 May 2020; Published: 20 May 2020 Abstract: Conopeptides belonging to the A-superfamily from the venomous molluscs, Conus, are typically α-conotoxins. The α-conotoxins are of interest as therapeutic leads and pharmacological tools due to their selectivity and potency at nicotinic acetylcholine receptor (nAChR) subtypes. Structurally, the α-conotoxins have a consensus fold containing two conserved disulfide bonds that define the two-loop framework and brace a helical region. Here we report on a novel α-conotoxin Pl168, identified from the transcriptome of Conus planorbis, which has an unusual 4/8 loop framework.
    [Show full text]
  • Conotoxins As Tools to Understand the Physiological Function of Voltage-Gated Calcium (Cav) Channels
    marine drugs Review Conotoxins as Tools to Understand the Physiological Function of Voltage-Gated Calcium (CaV) Channels David Ramírez 1,2, Wendy Gonzalez 1,3, Rafael A. Fissore 4 and Ingrid Carvacho 5,* 1 Centro de Bioinformática y Simulación Molecular, Universidad de Talca, 3460000 Talca, Chile; davramirez@utalca.cl (D.R.); wgonzalez@utalca.cl (W.G.) 2 Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, 3460000 Talca, Chile 3 Millennium Nucleus of Ion Channels-Associated Diseases (MiNICAD), Universidad de Talca, 3460000 Talca, Chile 4 Department of Veterinary and Animal Sciences, University of Massachusetts, Amherst, MA 01003, USA; rfissore@umass.edu 5 Department of Biology and Chemistry, Faculty of Basic Sciences, Universidad Católica del Maule, 3480112 Talca, Chile * Correspondence: icarvacho@ucm.cl; Tel.: +56-71-220-3518 Received: 8 August 2017; Accepted: 4 October 2017; Published: 13 October 2017 Abstract: Voltage-gated calcium (CaV) channels are widely expressed and are essential for the completion of multiple physiological processes. Close regulation of their activity by specific inhibitors and agonists become fundamental to understand their role in cellular homeostasis as well as in human tissues and organs. CaV channels are divided into two groups depending on the membrane potential required to activate them: High-voltage activated (HVA, CaV1.1–1.4; CaV2.1–2.3) and Low-voltage activated (LVA, CaV3.1–3.3). HVA channels are highly expressed in brain (neurons), heart, and adrenal medulla (chromaffin cells), among others, and are also classified into subtypes which can be distinguished using pharmacological approaches. Cone snails are marine gastropods that capture their prey by injecting venom, “conopeptides”, which cause paralysis in a few seconds.
    [Show full text]
  • Voltage-Gated Sodium Channels and Blockers: an Overview and Where Will They Go?*
    Current Medical Science 39(6):863-873,2019 DOICurrent https://doi.org/10.1007/s11596-019-2117-0 Medical Science 39(6):2019 863 Voltage-gated Sodium Channels and Blockers: An Overview and Where Will They Go?* Zhi-mei LI1, Li-xia CHEN2#, Hua LI1# 1Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China 2Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China Huazhong University of Science and Technology 2019 Summary: Voltage-gated sodium (Nav) channels are critical players in the generation and propagation of action potentials by triggering membrane depolarization. Mutations in Nav channels are associated with a variety of channelopathies, which makes them relevant targets for pharmaceutical intervention. So far, the cryoelectron microscopic structure of the human Nav1.2, Nav1.4, and Nav1.7 has been reported, which sheds light on the molecular basis of functional mechanism of Nav channels and provides a path toward structure-based drug discovery. In this review, we focus on the recent advances in the structure, molecular mechanism and modulation of Nav channels, and state updated sodium channel blockers for the treatment of pathophysiology disorders and briefly discuss where the blockers may be developed in the future. Key words: voltage-gated sodium channels; blockers; Nav channel structures; channelopathies Life did not come into existence until living In this review, we focus on voltage-gated organisms were enclosed by one or more membranes sodium (Nav) channels, which selectively conduct which cut them off from the chaotic world at a sodium ions movement in response to variations of molecular level.
    [Show full text]
  • Centipede Venoms As a Source of Drug Leads
    Title Centipede venoms as a source of drug leads Authors Undheim, EAB; Jenner, RA; King, GF Description peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation? show=aimsScope&journalCode=iedc20 Date Submitted 2016-12-14 Centipede venoms as a source of drug leads Eivind A.B. Undheim1,2, Ronald A. Jenner3, and Glenn F. King1,* 1Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia 2Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia 3Department of Life Sciences, Natural History Museum, London SW7 5BD, UK Main text: 4132 words Expert Opinion: 538 words References: 100 *Address for correspondence: glenn.king@imb.uq.edu.au (Phone: +61 7 3346-2025) 1 Centipede venoms as a source of drug leads ABSTRACT Introduction: Centipedes are one of the oldest and most successful lineages of venomous terrestrial predators. Despite their use for centuries in traditional medicine, centipede venoms remain poorly studied. However, recent work indicates that centipede venoms are highly complex chemical arsenals that are rich in disulfide-constrained peptides that have novel pharmacology and three-dimensional structure. Areas covered: This review summarizes what is currently know about centipede venom proteins, with a focus on disulfide-rich peptides that have novel or unexpected pharmacology that might be useful from a therapeutic perspective. We also highlight the remarkable diversity of constrained three- dimensional peptide scaffolds present in these venoms that might be useful for bioengineering of drug leads. Expert opinion: The resurgence of interest in peptide drugs has stimulated interest in venoms as a source of highly stable, disulfide-constrained peptides with potential as therapeutics.
    [Show full text]
  • Biological Agent Reference Sheet (BARS)- Conotoxin
    Biological Agent Reference Sheet (BARS) This content of this document is for Emory University USE ONLY. The information and contents of this Biological Agent Reference Sheet (including all text and graphics), whether available in print or electronic format (including any digital format, e-mail transmissions, or download from the website), shall be known hereinafter as “Reference Sheet Content”. The Reference Sheet Content is provided as a courtesy and is not intended as a sole source of guidance in the evaluation of Biological Agents. The Reference Sheet Content is not intended to substitute for medical advice, medical care, diagnosis or treatment obtained from a physician or health care provider. Please seek the advice of a physician or other qualified health provider with any questions you may have regarding a medical condition. Do not rely on the Reference Sheet Content for diagnosis, treatment, or medical advice. This Reference Sheet Content is for informational purposes and does not provide individualized medical care or treatment. No endorsement of any specific tests, products, or procedures is made by Reference Sheet Content or affiliated party, member, agent or employee of the Emory University Environmental Health and Safety Office. 1762 Clifton Road, Suite 1200 Atlanta, Georgia 30322 (404) 727-5922 FAX: (404) 727-9778 BIOLOGICAL AGENT REFERENCE SHEET Conotoxin CHARACTERISTICS SPILL PROCEDURES Neurotoxic venom naturally produced by the Conus Notify others working in the lab. Rinse gloves with Natural Source genus of gastropod mollusks decontamination solution and don new gloves. Laboratory Cover area of the spill with paper towels and apply Isolated toxin Source decontamination solution, working from the Conotoxins are polypeptides comprised of 10-30 Small perimeter towards the center.
    [Show full text]
  • Botulinum Toxin
    Botulinum toxin From Wikipedia, the free encyclopedia Jump to: navigation, search Botulinum toxin Clinical data Pregnancy ? cat. Legal status Rx-Only (US) Routes IM (approved),SC, intradermal, into glands Identifiers CAS number 93384-43-1 = ATC code M03AX01 PubChem CID 5485225 DrugBank DB00042 Chemical data Formula C6760H10447N1743O2010S32 Mol. mass 149.322,3223 kDa (what is this?) (verify) Bontoxilysin Identifiers EC number 3.4.24.69 Databases IntEnz IntEnz view BRENDA BRENDA entry ExPASy NiceZyme view KEGG KEGG entry MetaCyc metabolic pathway PRIAM profile PDB structures RCSB PDB PDBe PDBsum Gene Ontology AmiGO / EGO [show]Search Botulinum toxin is a protein and neurotoxin produced by the bacterium Clostridium botulinum. Botulinum toxin can cause botulism, a serious and life-threatening illness in humans and animals.[1][2] When introduced intravenously in monkeys, type A (Botox Cosmetic) of the toxin [citation exhibits an LD50 of 40–56 ng, type C1 around 32 ng, type D 3200 ng, and type E 88 ng needed]; these are some of the most potent neurotoxins known.[3] Popularly known by one of its trade names, Botox, it is used for various cosmetic and medical procedures. Botulinum can be absorbed from eyes, mucous membranes, respiratory tract or non-intact skin.[4] Contents [show] [edit] History Justinus Kerner described botulinum toxin as a "sausage poison" and "fatty poison",[5] because the bacterium that produces the toxin often caused poisoning by growing in improperly handled or prepared meat products. It was Kerner, a physician, who first conceived a possible therapeutic use of botulinum toxin and coined the name botulism (from Latin botulus meaning "sausage").
    [Show full text]
  • The Block of Shaker K Channels by -Conotoxin PVIIA Is State Dependent
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by PubMed Central The Block of Shaker K1 Channels by k-Conotoxin PVIIA Is State Dependent Heinrich Terlau,* Anna Boccaccio,* Baldomero M. Olivera,‡ and Franco Conti§ From the *Max-Planck-Institut für Experimentelle Medizin, 37075 Göttingen, Germany; ‡Department of Biology, University of Utah, Salt Lake City, Utah 84112; and §Istituto di Cibernetica e Biofisica, Consiglio Nazionale delle Ricerche, 16149 Genova, Italy abstract k-conotoxin PVIIA is the first conotoxin known to interact with voltage-gated potassium channels by inhibiting Shaker-mediated currents. We studied the mechanism of inhibition and concluded that PVIIA blocks the ion pore with a 1:1 stoichiometry and that binding to open or closed channels is very different. Open-channel properties are revealed by relaxations of partial block during step depolarizations, whereas double-pulse protocols 1 characterize the slower reequilibration of closed-channel binding. In 2.5 mM-[K ]o, the IC50 rises from a tonic value of z50 to z200 nM during openings at 0 mV, and it increases e-fold for about every 40-mV increase in volt- age. The change involves mainly the voltage dependence and a 20-fold increase at 0 mV of the rate of PVIIA disso- ciation, but also a fivefold increase of the association rate. PVIIA binding to Shaker D6-46 channels lacking N-type inactivation or to wild phenotypes appears similar, but inactivation partially protects the latter from open-channel 1 unblock. Raising [K ]o to 115 mM has little effect on open-channel binding, but increases almost 10-fold the tonic IC50 of PVIIA due to a decrease by the same factor of the toxin rate of association to closed channels.
    [Show full text]