Tutorial on Moa Mechanisms

Total Page:16

File Type:pdf, Size:1020Kb

Tutorial on Moa Mechanisms Insecticide Mode of Action Training slide deck IRAC MoA Workgroup Version 1.0, April 2019 1 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright What is an Insecticide’s ‘Mode of Action’? The Mode of action defines the process of how an insecticide works on an insect or mite at a molecular level Why is it good to know the Mode of Action of an Insecticide? Knowing the Mode of action of an insecticide is key to managing resistance The Insecticide Resistance Action Committee (IRAC) is a coordinated industry response to resistance management 2 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright ADME is an important factor in an insecticide’s bioavailability n Absorption q Through the cuticle q Orally through consumption q Inhaled through spiracles as vapor n Distribution Metabolic q Through the body to target sites Enzymes n Metabolism (Break down) q By insect defense mechanisms n Excretion 3 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides act on key functional proteins that regulate vital processes Target protein e.g. ion channel binding pocket Small molecule insecticide Insecticides act on key functional proteins that regulate vital processes Altered protein function 1. A protein can have more than one binding pocket for small molecules Altered 2. Specific binding pockets can accommodate biological chemicals with different structures response 4 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The Pro-Insecticide concept A Pro-Insecticide might have negligible activity on the target protein due to protecting groups, but can get metabolized in vivo to its active form. This can be a tool to: • Improve bioavailability Pro-Insecticide Metabolic Enzyme(s) • Enable selective toxicity Insecticide Target protein Altered protein function 5 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Major mechanisms of Insecticide Resistance Metabolic Resistance Metabolic Enzymes and/or Target Insecticide protein Target Site Resistance Insecticide Genetic modifications of Altered Target the target that interfere with target protein binding of the Insecticide protein 6 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Key functional proteins that are targets for Insecticides Ion channels Enzymes Receptors essential for signal biocatalysts bioelectricity transducer ligand + Na+ Ca2+ K+ - or Cl Proteins accelerating chemical reactions Binding of a ligand triggers a response 7 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticide Mode of Action Major classes Nerve & Muscle Growth Respiration Midgut Unknown or Non-Specific 8 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Ion channels are important targets of neuromuscular disruptors Na+ Ca2+ Cl- Cells are surrounded by a cell membrane, which acts - - - like an insulator separating two conducting media K+ Large organic An asymmetric separation of charges across the cell anions membrane makes the inside negative compared to the outside of the cell (membrane potential) Ion channels are pore-forming membrane Na+, Ca2+ proteins that transduce signals by controlling the flux or Cl- of ions across the cell membrane. Their concentration gradients together with the membrane potential • Gating: Trigger for channel determine the direction of ion flux. opening (voltage, ligand, etc.) • Ion selectivity: Ion preference In electrically excitable cells (neurons, muscle cells) of the channel ion channels play an important role in fast signal transduction over long distances 9 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The Insect Neuromuscular system: Translating a stimulus into (muscle) action Muscle Stimulus ? 10 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Different types of neurons are involved in signal transduction and fine tuning Muscle Stimulus CNS modulatory Ganglion neuron The Central Nervous System (CNS) is the insect’s control center sensory neuron interneuron inhibitory neuron motoneuron 11 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Ion channels play diverse roles within the neuromuscular system Muscle CNS Ganglion 12 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Overview of ion channels targeted by neuromuscular disruptors Muscle CNS Ganglion 13 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright The TRPV channels exist in specialized sensory neurons that detect stretch Muscle CNS modulatory Ganglion neuron Na+, Ca2+ TRPV sensory neuron interneuron inhibitory neuron motoneuron 14 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright TRPV channels play an important role in insect stretch receptor signaling (Chordotonal Organ) • Sight Stimulus • Taste • Smell • Touch • Hearing (antenna) Sensed by • Gravity (antenna) • Proprioception* (joints) stretch receptors • Others sensory neuron *Proprioception is the detection of the relative position and motion of body parts When a doctor tests Insects also have stretch reflexes with a rubber receptors that detect joint hammer (knee jerk reflex) bending forces local stretch receptors are activated that signal to the spinal cord and back to the target muscle. 15 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides acting on TRPV channels interfere with stretch receptor signaling n TRPV channel modulators affect Chordotonal organs (COs), stretch receptors in the insect joints that sense relative position of body parts (proprioception) Leg extension caused by a TRPV modulator (can be imagined as a ‘molecular’ rubber hammer) n TRPV channels amplify the weak mechanosensory signal in chordotonal neurons 1. Signal detection 2. Signal amplification Mechano- sensory TRPV channel n Modulation of TRPV channels generates continuous chordotonal nerve signals independent of joint movement. This leaves insects deaf and uncoordinated, resulting in rapid feeding cessation, leading to starvation and ultimately death 16 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright TRPV channel and chordotonal organ modulators Group 9: Chordotonal Group 29: organ TRPV channel modulators Chordotonal organ modulators – undefined target site Pymetrozine Flonicamid 9B Pyridine Pyrifluquinazon Afidopyropen azomethine derivatives 9D Pyropenes 29 Flonicamid Flonicamid produces symptoms similar to TRPV channel modulators and like its more active metabolite affects chordotonal organs. However, Flonicamid appears not to act directly on TRPV channels, suggesting a different target site in chordotonal organs. 17 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Overview of ion channels targeted by neuromuscular disruptors Muscle CNS Ganglion 18 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Insecticides acting on Sodium channels Muscle CNS modulatory Ganglion neuron Na+ Sodium Channel sensory neuron interneuron inhibitory neuron motoneuron 19 Details are accurate to the best of our knowledge but IRAC and its member companies cannot accept responsibility for how the information is used or interpreted. Protected by © Copyright Sodium channels play a crucial role in signal propagation in excitable cells Axons are long cable-like parts of the neuron that carry electrical signals to a junction with another cell Na+ Voltage-dependent sodium Sodium channels contain
Recommended publications
  • Combined Pharmacological Administration of AQP1 Ion Channel
    www.nature.com/scientificreports OPEN Combined pharmacological administration of AQP1 ion channel blocker AqB011 and water channel Received: 15 November 2018 Accepted: 13 August 2019 blocker Bacopaside II amplifes Published: xx xx xxxx inhibition of colon cancer cell migration Michael L. De Ieso 1, Jinxin V. Pei 1, Saeed Nourmohammadi1, Eric Smith 1,2, Pak Hin Chow1, Mohamad Kourghi1, Jennifer E. Hardingham 1,2 & Andrea J. Yool 1 Aquaporin-1 (AQP1) has been proposed as a dual water and cation channel that when upregulated in cancers enhances cell migration rates; however, the mechanism remains unknown. Previous work identifed AqB011 as an inhibitor of the gated human AQP1 cation conductance, and bacopaside II as a blocker of AQP1 water pores. In two colorectal adenocarcinoma cell lines, high levels of AQP1 transcript were confrmed in HT29, and low levels in SW480 cells, by quantitative PCR (polymerase chain reaction). Comparable diferences in membrane AQP1 protein levels were demonstrated by immunofuorescence imaging. Migration rates were quantifed using circular wound closure assays and live-cell tracking. AqB011 and bacopaside II, applied in combination, produced greater inhibitory efects on cell migration than did either agent alone. The high efcacy of AqB011 alone and in combination with bacopaside II in slowing HT29 cell motility correlated with abundant membrane localization of AQP1 protein. In SW480, neither agent alone was efective in blocking cell motility; however, combined application did cause inhibition of motility, consistent with low levels of membrane AQP1 expression. Bacopaside alone or combined with AqB011 also signifcantly impaired lamellipodial formation in both cell lines. Knockdown of AQP1 with siRNA (confrmed by quantitative PCR) reduced the efectiveness of the combined inhibitors, confrming AQP1 as a target of action.
    [Show full text]
  • Pain-Enhancing Mechanism Through Interaction Between TRPV1 and Anoctamin 1 in Sensory Neurons
    Pain-enhancing mechanism through interaction between TRPV1 and anoctamin 1 in sensory neurons Yasunori Takayamaa, Daisuke Utab, Hidemasa Furuec,d, and Makoto Tominagaa,d,1 aDivision of Cell Signaling, Okazaki Institute for Integrative Bioscience, Okazaki 444-8787, Japan; bDepartment of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan; cDivision of Neural Signaling, National Institute for Physiological Sciences, Okazaki 444-8787, Japan; and dDepartment of Physiological Sciences, Graduate University for Advanced Studies, Okazaki 444-8787, Japan Edited by David Julius, University of California, San Francisco, CA, and approved March 20, 2015 (received for review November 11, 2014) The capsaicin receptor transient receptor potential cation channel channels. Mammalian TRPV1 is activated by noxious heat, acid, and vanilloid 1 (TRPV1) is activated by various noxious stimuli, and the many chemical compounds including capsaicin (16–18). The calcium stimuli are converted into electrical signals in primary sensory permeability of TRPV1 is more than 10 times that of sodium, neurons. It is believed that cation influx through TRPV1 causes suggesting that TRPV1 could activate anoctamins readily, leading depolarization, leading to the activation of voltage-gated sodium to further depolarization. ANO1 plays an important role in noci- channels, followed by the generation of action potential. Here we ception in primary sensory neurons (19), and bradykinin-induced report that the capsaicin-evoked action potential could be induced and neuropathic pain-related behaviors were reduced in ANO1 by two components: a cation influx-mediated depolarization caused conditional-knockout mice (20, 21), suggesting that interaction be- by TRPV1 activation and a subsequent anion efflux-mediated de- tween the two proteins could strongly enhance nociceptive signals.
    [Show full text]
  • Ion Channels of Nociception
    International Journal of Molecular Sciences Editorial Ion Channels of Nociception Rashid Giniatullin A.I. Virtanen Institute, University of Eastern Finland, 70211 Kuopio, Finland; Rashid.Giniatullin@uef.fi; Tel.: +358-403553665 Received: 13 May 2020; Accepted: 15 May 2020; Published: 18 May 2020 Abstract: The special issue “Ion Channels of Nociception” contains 13 articles published by 73 authors from different countries united by the main focusing on the peripheral mechanisms of pain. The content covers the mechanisms of neuropathic, inflammatory, and dental pain as well as pain in migraine and diabetes, nociceptive roles of P2X3, ASIC, Piezo and TRP channels, pain control through GPCRs and pharmacological agents and non-pharmacological treatment with electroacupuncture. Keywords: pain; nociception; sensory neurons; ion channels; P2X3; TRPV1; TRPA1; ASIC; Piezo channels; migraine; tooth pain Sensation of pain is one of the fundamental attributes of most species, including humans. Physiological (acute) pain protects our physical and mental health from harmful stimuli, whereas chronic and pathological pain are debilitating and contribute to the disease state. Despite active studies for decades, molecular mechanisms of pain—especially of pathological pain—remain largely unaddressed, as evidenced by the growing number of patients with chronic forms of pain. There are, however, some very promising advances emerging. A new field of pain treatment via neuromodulation is quickly growing, as well as novel mechanistic explanations unleashing the efficiency of traditional techniques of Chinese medicine. New molecular actors with important roles in pain mechanisms are being characterized, such as the mechanosensitive Piezo ion channels [1]. Pain signals are detected by specialized sensory neurons, emitting nerve impulses encoding pain in response to noxious stimuli.
    [Show full text]
  • The Cys-Loop Ligand-Gated Ion Channel Gene Superfamily of the Parasitoid Wasp, Nasonia Vitripennis
    Heredity (2010) 104, 247–259 & 2010 Macmillan Publishers Limited All rights reserved 0018-067X/10 $32.00 www.nature.com/hdy ORIGINAL ARTICLE The cys-loop ligand-gated ion channel gene superfamily of the parasitoid wasp, Nasonia vitripennis AK Jones, AN Bera, K Lees and DB Sattelle MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK Members of the cys-loop ligand-gated ion channel (cysLGIC) Nasonia possesses ion channels predicted to be gated superfamily mediate chemical neurotransmission and by acetylcholine, g-amino butyric acid, glutamate and are studied extensively as potential targets of drugs used histamine, as well as orthologues of the Drosophila to treat neurological disorders, such as Alzheimer’s disease. pH-sensitive chloride channel (pHCl), CG8916 and Insect cys-loop LGICs also have central roles in the nervous CG12344. Similar to other insects, wasp cysLGIC diversity system and are targets of highly successful insecticides. is broadened by alternative splicing and RNA A-to-I editing, Here, we describe the cysLGIC superfamily of the parasitoid which may also serve to generate species-specific recep- wasp, Nasonia vitripennis, which is emerging as a highly tor isoforms. These findings on N. vitripennis enhance useful model organism and is deployed as a biological our understanding of cysLGIC functional genomics and control of insect pests. The wasp superfamily consists of 26 provide a useful basis for the study of their function in the genes, which is the largest insect cysLGIC superfamily wasp model, as well as for the development of improved characterized, whereas Drosophila melanogaster, Apis insecticides that spare a major beneficial insect species.
    [Show full text]
  • The ATP-Releasing Maxi-Cl Channel: Its Identity, Molecular Partners, and Physiological/Pathophysiological Implications
    life Review The ATP-Releasing Maxi-Cl Channel: Its Identity, Molecular Partners, and Physiological/Pathophysiological Implications Ravshan Z. Sabirov 1,2,*, Md. Rafiqul Islam 1,3, Toshiaki Okada 1,4, Petr G. Merzlyak 1,2 , Ranokhon S. Kurbannazarova 1,2, Nargiza A. Tsiferova 1,2 and Yasunobu Okada 1,5,6,* 1 Division of Cell Signaling, National Institute for Physiological Sciences (NIPS), Okazaki 444-8787, Japan; rafi[email protected] (M.R.I.); [email protected] (T.O.); [email protected] (P.G.M.); [email protected] (R.S.K.); [email protected] (N.A.T.) 2 Institute of Biophysics and Biochemistry, National University of Uzbekistan, Tashkent 100174, Uzbekistan 3 Department of Biochemistry and Molecular Biology, Jagannath University, Dhaka 1100, Bangladesh 4 Veneno Technologies Co. Ltd., Tsukuba 305-0031, Japan 5 Department of Physiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan 6 Department of Physiology, School of Medicine, Aichi Medical University, Nagakute 480-1195, Japan * Correspondence: [email protected] (R.Z.S.); [email protected] (Y.O.); Tel.: +81-46-858-1501 (Y.O.); Fax: +81-46-858-1542 (Y.O.) Abstract: The Maxi-Cl phenotype accounts for the majority (app. 60%) of reports on the large- conductance maxi-anion channels (MACs) and has been detected in almost every type of cell, including placenta, endothelium, lymphocyte, cardiac myocyte, neuron, and glial cells, and in cells originating from humans to frogs. A unitary conductance of 300–400 pS, linear current-to- Citation: Sabirov, R.Z.; Islam, M..R.; voltage relationship, relatively high anion-to-cation selectivity, bell-shaped voltage dependency, Okada, T.; Merzlyak, P.G.; and sensitivity to extracellular gadolinium are biophysical and pharmacological hallmarks of the Kurbannazarova, R.S.; Tsiferova, Maxi-Cl channel.
    [Show full text]
  • Beyond Water Homeostasis: Diverse Functional Roles of Mammalian Aquaporins Philip Kitchena, Rebecca E. Dayb, Mootaz M. Salmanb
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Aston Publications Explorer © 2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ Beyond water homeostasis: Diverse functional roles of mammalian aquaporins Philip Kitchena, Rebecca E. Dayb, Mootaz M. Salmanb, Matthew T. Connerb, Roslyn M. Billc and Alex C. Connerd* aMolecular Organisation and Assembly in Cells Doctoral Training Centre, University of Warwick, Coventry CV4 7AL, UK bBiomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, UK cSchool of Life & Health Sciences and Aston Research Centre for Healthy Ageing, Aston University, Aston Triangle, Birmingham, B4 7ET, UK dInstitute of Clinical Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK * To whom correspondence should be addressed: Alex C. Conner, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. 0044 121 415 8809 ([email protected]) Keywords: aquaporin, solute transport, ion transport, membrane trafficking, cell volume regulation The abbreviations used are: GLP, glyceroporin; MD, molecular dynamics; SC, stratum corneum; ANP, atrial natriuretic peptide; NSCC, non-selective cation channel; RVD/RVI, regulatory volume decrease/increase; TM, transmembrane; ROS, reactive oxygen species 1 Abstract BACKGROUND: Aquaporin (AQP) water channels are best known as passive transporters of water that are vital for water homeostasis. SCOPE OF REVIEW: AQP knockout studies in whole animals and cultured cells, along with naturally occurring human mutations suggest that the transport of neutral solutes through AQPs has important physiological roles. Emerging biophysical evidence suggests that AQPs may also facilitate gas (CO2) and cation transport.
    [Show full text]
  • Inward-Rectifier Chloride Currents in Reissner's
    INWARD-RECTIFIER CHLORIDE CURRENTS IN REISSNER’S MEMBRANE EPITHELIAL CELLS by KYUNGHEE KIM B.S., Sookmyung Women’s University, Seoul, South Korea 1999-2003 M.S., KAIST (Korea Advanced Institute of Science and Technology), Daejeon, South Korea 2003-2005 A THESIS submitted in partial fulfillment of the requirements for the degree MASTER OF SCIENCE Department of Anatomy and Physiology College of Veterinary Medicine KANSAS STATE UNIVERSITY Manhattan, Kansas 2010 Approved by: Major Professor Dr. Daniel C. Marcus Abstract Sensory transduction in the cochlea depends on regulated ion secretion and absorption. Results of whole-organ experiments suggested that Reissner’s membrane may play a role in the control of luminal Cl-. We tested for the presence of Cl- transport pathways in isolated mouse Reissner’s membrane using whole-cell patch clamp recordings and gene transcript analyses using RT-PCR. The current-voltage (I-V) relationship in the presence of symmetrical NMDG-Cl was strongly inward-rectifying at negative voltages, with a small outward current at positive voltages. The inward-rectifying component of the I-V curve had several properties similar to those of the ClC- 2 Cl- channel. It was stimulated by extracellular acidity and inhibited by extracellular Cd2+, Zn2+, and intracellular ClC-2 antibody. Channel transcripts expressed in Reissner’s membrane include ClC-2, Slc26a7 and ClC-Ka, but not Cftr, ClC-1, ClCa1, ClCa2, ClCa3, ClCa4, Slc26a9, ClC-Kb, Best1, Best2, Best3 or the beta-subunit of ClC-K, barttin. ClC-2 is the only molecularly-identified channel present that is a strong inward rectifier. This thesis incorporates the publication by KX Kim and DC Marcus, Inward-rectifier chloride currents in Reissner’s membrane epithelial cells, Biochem.
    [Show full text]
  • The Biology of Clc Chloride Channels Alfred L
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector R620 Review From stones to bones: The biology of ClC chloride channels Alfred L. George, Jr, Laura Bianchi, Elizabeth M. Link and Carlos G. Vanoye Chloride (Cl–) is the most abundant extracellular anion in Introduction multicellular organisms. Passive movement of Cl– Ion channels are ubiquitous transmembrane proteins that through membrane ion channels enables several cellular confer selective ionic permeability to cell surface and intra- and physiological processes including transepithelial cellular membranes in virtually every cell in every known salt transport, electrical excitability, cell volume organism. Research on ion channels during the past 60 years regulation and acidification of internal and external has focused predominantly on proteins that mediate selec- compartments. One family of proteins mediating Cl– tive permeability to monovalent (Na+, K+) and divalent permeability, the ClC channels, has emerged as (Ca2+) cations. However, there has recently been intense important for all of these biological processes. The fascination with ion channels that are selectively permeable importance of ClC channels has in part been realized to chloride (Cl–) ions as their importance in human diseases through studies of inherited human diseases and and fundamental cellular events has been elucidated. genetically engineered mice that display a wide range of phenotypes from kidney stones to petrified bones. These Historically, chloride channels carrying electrical current recent findings have demonstrated many eclectic have been less exciting than their more dynamic cation functions of ClC channels and have placed Cl– channels channel counterparts. This is particularly evident in elec- in the physiological limelight.
    [Show full text]
  • The Contribution of Calcium-Activated Potassium Channel Dysfunction to Altered Purkinje Neuron Membrane Excitability in Spinocerebellar Ataxia
    The Contribution of Calcium-Activated Potassium Channel Dysfunction to Altered Purkinje Neuron Membrane Excitability in Spinocerebellar Ataxia by David D. Bushart A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Molecular and Integrative Physiology) in The University of Michigan 2018 Doctoral Committee: Professor Geoffrey G. Murphy, Co-Chair Associate Professor Vikram G. Shakkottai, Co-Chair Professor William T. Dauer Professor W. Michael King Professor Andrew P. Lieberman Professor Malcolm J. Low David D. Bushart [email protected] ORCiD: 0000-0002-3852-127X © David D. Bushart 2018 Acknowledgements I would like to acknowledge three groups which provided me with support and motivation to complete the studies in this dissertation, and for helping me keep my research efforts in perspective. First, I would like to acknowledge my friends and family. Their emotional support, and the time they have invested in supporting my growth as both a person and a scientist, cannot be overstated. I am eternally grateful to have a network of such caring people around me. Second, I would like to acknowledge cerebellar ataxia patients for their perseverance and positive outlook in the face of devastating circumstances. My ability to interact with patients at the National Ataxia Foundation meetings, along with the positive messages that my research efforts were met with, was my greatest motivating factor throughout the final years of my dissertation studies. I encourage other researchers to seek out similar interactions, as they will make for a more invested and focused scientist. Third, I would like to acknowledge the research animals used in the studies of this dissertation.
    [Show full text]
  • Characterization of Renal Chloride Channel (CLCN5) Mutations in Dent’S Disease
    J Am Soc Nephrol 11: 1460–1468, 2000 Characterization of Renal Chloride Channel (CLCN5) Mutations in Dent’s Disease KATSUSUKE YAMAMOTO,* JEREMY P. D. T. COX,* THOMAS FRIEDRICH,† PAUL T. CHRISTIE,*‡‡ MARTIN BALD,‡ PETER N. HOUTMAN,§ MARTA J. LAPSLEY,ʈ LUDWIG PATZER,¶ MICHEL TSIMARATOS,# WILLIAM G VAN’T HOFF,** KANJI YAMAOKA,†† THOMAS J. JENTSCH,† and RAJESH V. THAKKER*‡‡ *MRC Molecular Endocrinology Group, Hammersmith Hospital, London, United Kingdom; †ZMNH Centre for Molecular Neurobiology, University of Hamburg, Germany; ‡Department of Paediatric Nephrology, University of Essen, Germany; §Department of Paediatrics, Leicester Royal Infirmary, United Kingdom; ʈDepartment of Chemical Pathology and Metabolism, St Helier Hospital, Surrey, United Kingdom; ¶Children’s Hospital “Jussuf Ibrahim,” Friedrich-Schiller University, Jena, Germany; #Department of Paediatric Nephrology, Children’s Hospital of the Timone, Marseille, France; **Department of Paediatric Nephrology, Great Ormond Street Hospital, London, United Kingdom; ††Department of Paediatrics, Osaka Prefectural Hospital, Osaka, Japan; and ‡‡Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, United Kingdom. Abstract. Dent’s disease is an X-linked renal tubular disorder endonuclease or sequence-specific oligonucleotide hybridiza- characterized by low molecular weight proteinuria, hypercal- tion analysis and were not common polymorphisms. The ciuria, nephrocalcinosis, nephrolithiasis, and renal failure. The frameshift deletions and nonsense mutation predict truncated disease is caused by mutations in a renal chloride channel gene, and inactivated CLC-5. The effects of the putative missense CLCN5, which encodes a 746 amino acid protein (CLC-5), Asp601Val mutant CLC-5 were assessed by heterologous ex- with 12 to 13 transmembrane domains. In this study, an addi- pression in Xenopus oocytes, and this revealed a chloride tional six unrelated patients with Dent’s disease were identified conductance that was similar to that observed for wild-type and investigated for CLCN5 mutations by DNA sequence CLC-5.
    [Show full text]
  • Mitochondrial Chloride Channels – What Are They For?
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 584 (2010) 2085–2092 journal homepage: www.FEBSLetters.org Review Mitochondrial chloride channels – What are they for? Zuzana Tomaskova, Karol Ondrias * Institute of Molecular Physiology and Genetics, Centre of Excellence for Cardiovascular Research, Slovak Academy of Sciences and Molecular Medicine Center, Slovak Academy of Sciences, 83334 Bratislava, Slovakia article info abstract Article history: This minireview focuses on observation of the properties, functional significance, and modulation of Received 16 November 2009 single chloride channels in the mitochondrial inner membrane using two electrophysiological Revised 11 January 2010 methods – the patch-clamp and bilayer lipid membrane methods. Measurements of parameters Accepted 19 January 2010 such as conductance, ClÀ/K+ selectivity, voltage or pH dependence as well as their modulation by Available online 26 January 2010 endogenous and exogenous compounds using individual mitochondrial chloride channels result Edited by Adam Szewczyk in an unexpectedly wide range of values. This paper discusses the origin of this wide variety of chan- nel parameters and the possible involvement of these channels in mitochondrial membrane poten- tial oscillations, apoptosis, carrier function, and mitochondrial fusion and fission. Keywords: Bilayer lipid membrane Ó 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Chloride channel Mitochondria Patch-clamp Single channel property 1. Introduction myotonia, epilepsy, hyperekplexia, lysosomal storage disease, deafness, renal salt loss, kidney stones, and osteopetrosis A chloride channel is a membrane component that, after [1,2,4–10]. Several major classes of chloride channels have been opening, allows the passing of ClÀ ions across the membrane.
    [Show full text]
  • Calcium- and Voltage-Dependent Dual Gating ANO1 Is an Intrinsic Determinant of Repolarization in Rod Bipolar Cells of the Mouse Retina
    cells Article Calcium- and Voltage-Dependent Dual Gating ANO1 is an Intrinsic Determinant of Repolarization in Rod Bipolar Cells of the Mouse Retina 1, 1, 1,2, Sun-Sook Paik y, Yong Soo Park y and In-Beom Kim * 1 Department of Anatomy, College of Medicine, The Catholic University of Korea, Seoul 100744, Korea; [email protected] (S.-S.P.); [email protected] (Y.S.P.) 2 Catholic Institute for Applied Anatomy, College of Medicine, The Catholic University of Korea, Seoul 100744, Korea * Correspondence: [email protected]; Tel.: +82-2-2258-7263; Fax: +82-2-536-3110 These authors contributed equally to this work. y Received: 17 January 2020; Accepted: 24 February 2020; Published: 26 February 2020 2+ Abstract: TMEM16A/anoctamin1 (ANO1), a calcium (Ca )-activated chloride (Cl−) channel, has many functions in various excitable cells and modulates excitability in both Ca2+- and voltage-gating modes. However, its gating characteristics and role in primary neural cells remain unclear. Here, we characterized its Ca2+- and voltage-dependent components in rod bipolar cells using dissociated and slice preparations of the mouse retina. The I-V curves of Ca2+-dependent ANO1 tail current and voltage-gated Ca2+ channel (VGCC) are similar; as ANO1 is blocked by VGCC inhibitors, ANO1 may be gated by Ca2+ influx through VGCC. The voltage-dependent component of ANO1 has outward rectifying and sustained characteristics and is clearly isolated by the inhibitory effect of Cl− reduction and T16Ainh-A01, a selective ANO1 inhibitor, in high EGTA, a Ca2+ chelator. The voltage-dependent component disappears due to VGCC inhibition, suggesting that Ca2+ is the essential trigger for ANO1.
    [Show full text]