DOCSLIB.ORG

Masarykova Univerzita V Brně

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Masarykova Univerzita V Brně MASARYKOVA UNIVERZITA PEDAGOGICKÁ FAKULTA Katedra fyziky, chemie a odborného vzdělávání Biologické jedy v ţivočišné říši Bakalářská práce Brno 2015 Vedoucí práce: Autor práce: Mgr. Petr Ptáček, Ph.D. Markéta Seborská Prohlášení Prohlašuji, že jsem předloženou bakalářskou práci vypracovala samostatně, s využitím pouze citovaných literárních pramenů, dalších informací a zdrojů v souladu s Disciplinárním řádem pro studenty Pedagogické fakulty Masarykovy univerzity a se zákonem č. 121/2000 Sb., o právu autorském, o právech souvisejících s právem autorským a o změně některých zákonů (autorský zákon), ve znění pozdějších předpisů. …………………………………. V Brně dne 31. března 2015 Markéta Seborská Poděkování Na tomto místě bych ráda poděkovala panu Mgr. Petru Ptáčkovi Ph.D., vedoucímu mé bakalářské práce, za trpělivé vedení a odbornou pomoc mé bakalářské práce. Anotace Bakalářská práce se zaměřuje na toxiny produkované ţivočichy. Věnuje se popisu mechanického účinku toxinů, příznaků intoxikace a terapie otravy. V práci jsou zahrnuty poznatky z toxikologie jako vědního oboru. Jedna kapitola je věnována i historii jedů. Tato práce bude výchozím materiálem pro diplomovou práci. Annotation The bachelor thesis focuses on the toxins produced by animals. It describes the mechanical effect of venoms, symptoms of intoxication and poisoning therapy. This bachelor thesis also includes knowledge of toxicology as a discipline. One chapter is devoted to the history of toxins. This work will be the starting material for a diploma thesis. Klíčová slova Toxikologie, ţivočichové, jedy, historie, otrava Keywords Toxicology, animals , poisons , history , poisoning Obsah ÚVOD .......................................................................................................................................................... 7 1 TOXIKOLOGIE .............................................................................................................................. 8 1.1 DĚLENÍ TOXIKOLOGIE .................................................................................................................... 8 1.1.1 Obecná toxikologie .............................................................................................................. 8 1.1.2 Analytická toxikologie .......................................................................................................... 8 1.1.3 Ekotoxikologie ...................................................................................................................... 9 1.1.4 Experimentální toxikologie .................................................................................................. 9 1.1.5 Klinická toxikologie ............................................................................................................. 9 1.1.6 Predikční toxikologie ........................................................................................................... 9 1.1.7 Průmyslová toxikologie ........................................................................................................ 9 1.1.8 Speciální toxikologie .......................................................................................................... 10 1.1.9 Farmaceutická toxikologie ................................................................................................. 10 1.1.10 Soudní toxikologie ......................................................................................................... 10 1.1.11 Veterinární toxikologie .................................................................................................. 10 1.1.12 Vojenská toxikologie...................................................................................................... 10 2 JED .................................................................................................................................................. 11 2.1 DÁVKA ......................................................................................................................................... 11 2.2 VNIKNUTÍ JEDU (LÁTKY) DO ORGANISMU ..................................................................................... 11 2.2.1 Inhalací – vdechováním přes respirační trakt .................................................................... 12 2.2.2 Resorpcí – vstřebáváním kůží nebo sliznicemi ................................................................... 12 2.2.3 Intravenózně – injekčně ...................................................................................................... 12 2.2.4 Per os – přes zažívací trakt ................................................................................................ 12 2.2.5 Per rektum – vstup konečníkem .......................................................................................... 13 2.2.6 Per uretram – vstup močovou trubicí ................................................................................. 13 2.3 VYLUČOVÁNÍ LÁTKY Z METABOLISMU ......................................................................................... 13 2.3.1 Vylučování přes kůži .......................................................................................................... 13 2.3.2 Vylučování ledvinami ......................................................................................................... 13 2.3.3 Vylučování játry ................................................................................................................. 14 2.3.4 Vylučování plícemi ............................................................................................................. 14 2.3.5 Vylučování do žaludku a střev ............................................................................................ 14 2.3.6 Vylučování stolicí ............................................................................................................... 14 2.3.7 Vylučování do mateřského mléka ....................................................................................... 14 3 TOXIKOLOGICKÉ TESTY ........................................................................................................ 15 3.1 AKUTNÍ TOXICITA – LD50, LC50 .................................................................................................... 15 3.2 SUBAKUTNÍ TOXICITA .................................................................................................................. 15 3.3 SUBCHRONICKÁ TOXICITA ............................................................................................................ 15 3.4 CHRONICKÁ TOXICITA .................................................................................................................. 16 4 MECHANISMUS TOXICKÉHO ÚČINKU ................................................................................ 17 4.1 INTERAKCE MEZI RECEPTOREM A LÁTKOU ................................................................................... 17 4.2 POŠKOZENÍ BUNĚČNÝCH MEMBRÁN ............................................................................................. 17 4.3 INTERFERENCE S TVORBOU BUNĚČNÉ ENERGIE ............................................................................ 18 4.4 VAZBA NA BIOMOLEKULY ............................................................................................................ 18 4.5 POŠKOZENÍ HOMEOSTÁZY VÁPNÍKU ............................................................................................. 18 4.6 ZÁSAH DO BUNĚČNÉHO CYKLU .................................................................................................... 19 5 HISTORIE ŢIVOČIŠNÝCH JEDŮ ............................................................................................. 20 5.1 STAROVĚK .................................................................................................................................... 20 5.2 STŘEDOVĚK .................................................................................................................................. 22 5.3 NOVOVĚK ..................................................................................................................................... 23 6 ŢIVOČIŠNÉ TOXINY ................................................................................................................... 24 6.1 KMEN ŢAHAVCI - CNIDARIA ......................................................................................................... 24 6.1.1 Jedový aparát ..................................................................................................................... 25 6.1.2 Medúzovci (Scyphozoa) ...................................................................................................... 25 6.1.3 Korálnatci (Anthozoa) ........................................................................................................ 26 6.2 KMEN MĚKKÝŠI – MOLLUSCA ...................................................................................................... 26 6.2.1 Plži – Gastropoda .............................................................................................................. 26 6.2.2 Mlži – Bivalvia ................................................................................................................... 27 6.2.3 Hlavonožci – Cephalopoda ................................................................................................ 29 6.3 KMEN ČLENOVCI - ARTHROPODA ................................................................................................ 31 6.3.1 Hmyz - Insecta ..................................................................................................................
Load more

Recommended publications
  • Using the Deadly M-Conotoxins As Probes of Voltage-Gated Sodium Channels
    Toxicon 44 (2004) 117–122 www.elsevier.com/locate/toxicon Mini-review Using the deadly m-conotoxins as probes of voltage-gated sodium channels Ronald A. Li*, Gordon F. Tomaselli The Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 871, Baltimore, MD 21205, USA Accepted 23 March 2004 Available online 19 June 2004 Abstract m-Conotoxins (m-CTX) are potent Na channel inhibitory peptides isolated from the venom of the predatory marine snail Conus geographus. m-CTXs exert their biological action by physically occluding the ion-conducting pore of voltage-gated Na (Nav) channels with a 1:1 stoichiometry in an all-or-none fashion. This article reviews our current knowledge of the mechanism of m-CTX and the associated structural and functional insights into its molecular target—Nav channels. q 2004 Elsevier Ltd. All rights reserved. Keywords: Na channel; Pore; m-Conotoxin Contents 1. Well-defined primary and 3-dimensional structures of m-CTX .............................. 117 2. Molecular target of m-CTX: voltage-gated Naþ channels . ................................. 119 3. m-CTX-pore interactions are site-specific.............................................. 119 4. Docking orientation of m-CTX ..................................................... 119 5. Isoform-specificity of m-CTX block ................................................. 121 6. m-CTX versus Kþ channel pore-blocking toxins ........................................ 121 7. Conclusion.................................................................... 121 Acknowledgements
    [Show full text]
  • Characterization of Functional Effects of Two New Active Fractions
    Basic and Clinical January, February 2019, Volume 10, Number 1 Research Paper: Characterization of Functional Effects of Two New Active Fractions Isolated From Scorpion Venom on Neuronal Ca2+ Spikes: A Possible Action on Ca2+- Dependent Dependent K+ Channels Hanieh Tamadon1, Zahra Ghasemi2 , Fatemeh Ghasemi1, Narges Hosseinmardi1, Hossein Vatanpour3, Mahyar Janahmadi1* 1. Department of Physiology, Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2. Department of Physiology, School of Medicine, Tarbiat Modares University, Tehran, Iran. 3. Department of Toxicology and Pharmacology, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Use your device to scan and read the article online Citation Tamadon, H., Ghasemi, Z., Ghasemi, F., Hosseinmardi, N., Vatanpour, H., & Janahmadi, M. (2019). Characterization of Functional Effects of Two New Active Fractions Isolated From Scorpion Venom on Neuronal Ca2+ Spikes: A Possible Action on Ca2+-Dependent Dependent K+ Channels. Basic and Clinical Neuroscience, 10(1), 49-58. http://dx.doi.org/10.32598/bcn.9.10.350 : http://dx.doi.org/10.32598/bcn.9.10.352 A B S T R A C T Introduction: It is a long time that natural toxin research is conducted to unlock the medical potential of toxins. Although venoms-toxins cause pathophysiological conditions, they may Article info: be effective to treat several diseases. Since toxins including scorpion toxins target voltage- Received: 26 Oct 2017 gated ion channels, they may have profound effects on excitable cells. Therefore, elucidating First Revision:10 Nov 2017 the cellular and electrophysiological impacts of toxins, particularly scorpion toxins would be Accepted: 30 Apr 2018 helpful in future drug development opportunities.
    [Show full text]
  • Medical Management of Biological Casualties Handbook
    USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Sixth Edition April 2005 U.S. ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES FORT DETRICK FREDERICK, MARYLAND Emergency Response Numbers National Response Center: 1-800-424-8802 or (for chem/bio hazards & terrorist events) 1-202-267-2675 National Domestic Preparedness Office: 1-202-324-9025 (for civilian use) Domestic Preparedness Chem/Bio Helpline: 1-410-436-4484 or (Edgewood Ops Center – for military use) DSN 584-4484 USAMRIID’s Emergency Response Line: 1-888-872-7443 CDC'S Emergency Response Line: 1-770-488-7100 Handbook Download Site An Adobe Acrobat Reader (pdf file) version of this handbook can be downloaded from the internet at the following url: http://www.usamriid.army.mil USAMRIID’s MEDICAL MANAGEMENT OF BIOLOGICAL CASUALTIES HANDBOOK Sixth Edition April 2005 Lead Editor Lt Col Jon B. Woods, MC, USAF Contributing Editors CAPT Robert G. Darling, MC, USN LTC Zygmunt F. Dembek, MS, USAR Lt Col Bridget K. Carr, MSC, USAF COL Ted J. Cieslak, MC, USA LCDR James V. Lawler, MC, USN MAJ Anthony C. Littrell, MC, USA LTC Mark G. Kortepeter, MC, USA LTC Nelson W. Rebert, MS, USA LTC Scott A. Stanek, MC, USA COL James W. Martin, MC, USA Comments and suggestions are appreciated and should be addressed to: Operational Medicine Department Attn: MCMR-UIM-O U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) Fort Detrick, Maryland 21702-5011 PREFACE TO THE SIXTH EDITION The Medical Management of Biological Casualties Handbook, which has become affectionately known as the "Blue Book," has been enormously successful - far beyond our expectations.
    [Show full text]
  • Report from the 26Th Meeting on Toxinology,“Bioengineering Of
    toxins Meeting Report Report from the 26th Meeting on Toxinology, “Bioengineering of Toxins”, Organized by the French Society of Toxinology (SFET) and Held in Paris, France, 4–5 December 2019 Pascale Marchot 1,* , Sylvie Diochot 2, Michel R. Popoff 3 and Evelyne Benoit 4 1 Laboratoire ‘Architecture et Fonction des Macromolécules Biologiques’, CNRS/Aix-Marseille Université, Faculté des Sciences-Campus Luminy, 13288 Marseille CEDEX 09, France 2 Institut de Pharmacologie Moléculaire et Cellulaire, Université Côte d’Azur, CNRS, Sophia Antipolis, 06550 Valbonne, France; [email protected] 3 Bacterial Toxins, Institut Pasteur, 75015 Paris, France; michel-robert.popoff@pasteur.fr 4 Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA de Saclay, Université Paris-Saclay, 91191 Gif-sur-Yvette, France; [email protected] * Correspondence: [email protected]; Tel.: +33-4-9182-5579 Received: 18 December 2019; Accepted: 27 December 2019; Published: 3 January 2020 1. Preface This 26th edition of the annual Meeting on Toxinology (RT26) of the SFET (http://sfet.asso.fr/ international) was held at the Institut Pasteur of Paris on 4–5 December 2019. The central theme selected for this meeting, “Bioengineering of Toxins”, gave rise to two thematic sessions: one on animal and plant toxins (one of our “core” themes), and a second one on bacterial toxins in honour of Dr. Michel R. Popoff (Institut Pasteur, Paris, France), both sessions being aimed at emphasizing the latest findings on their respective topics. Nine speakers from eight countries (Belgium, Denmark, France, Germany, Russia, Singapore, the United Kingdom, and the United States of America) were invited as international experts to present their work, and other researchers and students presented theirs through 23 shorter lectures and 27 posters.
    [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]
  • Glycine311, a Determinant of Paxilline Block in BK Channels: a Novel Bend in the BK S6 Helix Yu Zhou Washington University School of Medicine in St
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2010 Glycine311, a determinant of paxilline block in BK channels: A novel bend in the BK S6 helix Yu Zhou Washington University School of Medicine in St. Louis Qiong-Yao Tang Washington University School of Medicine in St. Louis Xiao-Ming Xia Washington University School of Medicine in St. Louis Christopher J. Lingle Washington University School of Medicine in St. Louis Follow this and additional works at: http://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Zhou, Yu; Tang, Qiong-Yao; Xia, Xiao-Ming; and Lingle, Christopher J., ,"Glycine311, a determinant of paxilline block in BK channels: A novel bend in the BK S6 helix." Journal of General Physiology.135,5. 481-494. (2010). http://digitalcommons.wustl.edu/open_access_pubs/2878 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Published April 26, 2010 A r t i c l e Glycine311, a determinant of paxilline block in BK channels: a novel bend in the BK S6 helix Yu Zhou, Qiong-Yao Tang, Xiao-Ming Xia, and Christopher J. Lingle Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110 The tremorogenic fungal metabolite, paxilline, is widely used as a potent and relatively specific blocker of Ca2+- and voltage-activated Slo1 (or BK) K+ channels. The pH-regulated Slo3 K+ channel, a Slo1 homologue, is resistant to blockade by paxilline.
    [Show full text]
  • Biosafety Manual 2017
    Biosafety Manual 2017 Revised 6/2017 Policy Statement It is the policy of Northern Arizona University (NAU) to provide a safe working environment. The primary responsibility for insuring safe conduct and conditions in the laboratory resides with the principal investigator. The Office of Biological Safety is committed to providing up-to-date information, training, and monitoring to the research and biomedical community concerning the safe conduct of biological, recombinant, and acute toxin research and the handling of biological materials in accordance with all pertinent local, state and federal regulations, guidelines, and laws. To that end, this manual is a resource, to be used in conjunction with the CDC and NIH guidelines, the NAU Select Agent Program, Biosafety in Microbiological and Biomedical Laboratories (BMBL), and other resource materials. Introduction This Biological Safety Manual is intended for use as a guidance document for researchers and clinicians who work with biological materials. It should be used in conjunction with the Laboratory-Specific Safety Manual, which provides more general safety information. These manuals describe policies and procedures that are required for the safe conduct of research at NAU. The NAU Personnel Policy on Safety 5.03 also provides guidance for safety in the workplace. Responsibilities In the academic research/teaching setting, the principal investigator (PI) is responsible for ensuring that all members of the laboratory are familiar with safe research practices. In the clinical laboratory setting, the faculty member who supervises the laboratory is responsible for safety practices. Lab managers, supervisors, technicians and others who provide supervisory roles in laboratories and clinical settings are responsible for overseeing the safety practices in laboratories and reporting any problems, accidents, and spills to the appropriate faculty member.
    [Show full text]
  • Ion Channels 3 1
    r r r Cell Signalling Biology Michael J. Berridge Module 3 Ion Channels 3 1 Module 3 Ion Channels Synopsis Ion channels have two main signalling functions: either they can generate second messengers or they can function as effectors by responding to such messengers. Their role in signal generation is mainly centred on the Ca2 + signalling pathway, which has a large number of Ca2+ entry channels and internal Ca2+ release channels, both of which contribute to the generation of Ca2 + signals. Ion channels are also important effectors in that they mediate the action of different intracellular signalling pathways. There are a large number of K+ channels and many of these function in different + aspects of cell signalling. The voltage-dependent K (KV) channels regulate membrane potential and + excitability. The inward rectifier K (Kir) channel family has a number of important groups of channels + + such as the G protein-gated inward rectifier K (GIRK) channels and the ATP-sensitive K (KATP) + + channels. The two-pore domain K (K2P) channels are responsible for the large background K current. Some of the actions of Ca2 + are carried out by Ca2+-sensitive K+ channels and Ca2+-sensitive Cl − channels. The latter are members of a large group of chloride channels and transporters with multiple functions. There is a large family of ATP-binding cassette (ABC) transporters some of which have a signalling role in that they extrude signalling components from the cell. One of the ABC transporters is the cystic − − fibrosis transmembrane conductance regulator (CFTR) that conducts anions (Cl and HCO3 )and contributes to the osmotic gradient for the parallel flow of water in various transporting epithelia.
    [Show full text]
  • Ion Channels: Structural Basis for Function and Disease
    UC Irvine UC Irvine Previously Published Works Title Ion channels: structural basis for function and disease. Permalink https://escholarship.org/uc/item/39x307jx Journal Seminars in perinatology, 20(6) ISSN 0146-0005 Author Goldstein, SA Publication Date 1996-12-01 DOI 10.1016/s0146-0005(96)80066-8 License https://creativecommons.org/licenses/by/4.0/ 4.0 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Ion Channels: Structural Basis for Function and Disease Steve A. N. Goldstein Ion channels are ubiquitous proteins that mediate nervous and muscular function, rapid transmem- brane signaling events, and ionic and fluid balance. The cloning of genes encoding ion channels has led to major strides in understanding the mechanistic basis for their function. These advances have shed light on the role of ion channels in normal physiology, clarified the molecular basis for an expanding number of diseases, and offered new direction to the development of rational therapeutic interventions. Copyright 1996 by W.B. Saunders Company on channels reside in the membranes of all by ion channels to be divided into two broad cells and control their electrical activity. 1 mechanistic groups: those resulting from loss of These proteins underlie subtle biological events channel function and those consequent to gain such as the response of a single rod cell to a of channel function. Three exemplary patho- beam of light, the activation of a T cell by its physiological correlates are examined, Long QT antigen, and the fast block to polyspermy of a syndrome, Liddle's syndrome and pseudohypo- fertilized ovum.
    [Show full text]
  • Androctonus Mauretanicus Mauretanicus
    Hindawi Publishing Corporation Journal of Toxicology Volume 2012, Article ID 103608, 9 pages doi:10.1155/2012/103608 Review Article Potassium Channels Blockers from the Venom of Androctonus mauretanicus mauretanicus Marie-France Martin-Eauclaire and Pierre E. Bougis Aix-Marseille University, CNRS, UMR 7286, CRN2M, Facult´edeM´edecine secteur Nord, CS80011, Boulevard Pierre Dramard, 13344 Marseille Cedex 15, France Correspondence should be addressed to Marie-France Martin-Eauclaire, [email protected] and Pierre E. Bougis, [email protected] Received 2 February 2012; Accepted 16 March 2012 Academic Editor: Maria Elena de Lima Copyright © 2012 M.-F. Martin-Eauclaire and P. E. Bougis. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. K+ channels selectively transport K+ ions across cell membranes and play a key role in regulating the physiology of excitable and nonexcitable cells. Their activation allows the cell to repolarize after action potential firing and reduces excitability, whereas channel inhibition increases excitability. In eukaryotes, the pharmacology and pore topology of several structural classes of K+ channels have been well characterized in the past two decades. This information has come about through the extensive use of scorpion toxins. We have participated in the isolation and in the characterization of several structurally distinct families of scorpion toxin peptides exhibiting different K+ channel blocking functions. In particular, the venom from the Moroccan scorpion Androctonus ffi + + mauretanicus mauretanicus provided several high-a nity blockers selective for diverse K channels (SKCa,Kv4.x, and Kv1.x K channel families).
    [Show full text]
  • Synergistic Antinociception by the Cannabinoid Receptor Agonist Anandamide and the PPAR-Α Receptor Agonist GW7647
    European Journal of Pharmacology 566 (2007) 117–119 www.elsevier.com/locate/ejphar Short communication Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647 Roberto Russo a, Jesse LoVerme b, Giovanna La Rana a, Giuseppe D'Agostino a, Oscar Sasso a, ⁎ Antonio Calignano a, Daniele Piomelli b, a Department of Experimental Pharmacology, University of Naples, Naples, Italy b Department of Pharmacology, 360 MSRII, University of California, Irvine, California 92697-4625, United States Received 9 December 2006; received in revised form 27 February 2007; accepted 6 March 2007 Available online 19 March 2007 Abstract The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-α (PPAR-α) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2- methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-α systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid. © 2007 Elsevier B.V.
    [Show full text]
  • Mechanism of M-Conotoxin PIIIA Binding to the Voltage-Gated Na+
    Mechanism of m-Conotoxin PIIIA Binding to the + Voltage-Gated Na Channel NaV1.4 Rong Chen*, Anna Robinson, Shin-Ho Chung Research School of Biology, Australian National University, Canberra, ACT, Australia Abstract + Several subtypes of voltage-gated Na (NaV) channels are important targets for pain management. m-Conotoxins isolated from venoms of cone snails are potent and specific blockers of different NaV channel isoforms. The inhibitory effect of m- conotoxins on NaV channels has been examined extensively, but the mechanism of toxin specificity has not been understood in detail. Here the known structure of m-conotoxin PIIIA and a model of the skeletal muscle channel NaV1.4 are used to elucidate elements that contribute to the structural basis of m-conotoxin binding and specificity. The model of NaV1.4 is constructed based on the crystal structure of the bacterial NaV channel, NaVAb. Six different binding modes, in which the side chain of each of the basic residues carried by the toxin protrudes into the selectivity filter of NaV1.4, are examined in atomic detail using molecular dynamics simulations with explicit solvent. The dissociation constants (Kd) computed for two selected binding modes in which Lys9 or Arg14 from the toxin protrudes into the filter of the channel are within 2 fold; both values in close proximity to those determined from dose response data for the block of NaV currents. To explore the mechanism of PIIIA specificity, a double mutant of NaV1.4 mimicking NaV channels resistant to m-conotoxins and tetrodotoxin is constructed and the binding of PIIIA to this mutant channel examined.
    [Show full text]