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nAChR elegans

Yan Hu, Melanie Miller, Bo Zhang, Thanh-Thanh Nguyen, Martin K Nielsen, Raffi V Aroian
BACKGROUND: The soil-transmitted nematodes (STNs) or helminths (hookworms, whipworms, large roundworms) infect the intestines of ~1.5 billion of the poorest peoples and are leading causes of morbidity worldwide. Only one class of anthelmintic or anti-nematode drugs, the benzimidazoles, is currently used in mass drug administrations, which is a dangerous situation. New anti-nematode drugs are urgently needed. Bacillus thuringiensis crystal protein Cry5B is a powerful, promising new candidate...
May 18, 2018: PLoS Neglected Tropical Diseases
Ashley A Martin, Janet E Richmond
Nicotinic acetylcholine receptors (nAChR) are present in many excitable tissues and are found both pre and post-synaptically. Through their non-specific cationic permeability, these nAChRs have excitatory roles in neurotransmission, neuromodulation, synaptic plasticity, and neuroprotection. Thus, nAChR mislocalization or functional deficits are associated with many neurological disease states. Therefore identifying the mechanisms that regulate nAChR expression and function will inform our understanding of normal as well as pathological physiological conditions and offer avenues for potential therapeutic advances...
February 24, 2018: Cell Calcium
Melanie Abongwa, Djordje S Marjanovic, James G Tipton, Fudan Zheng, Richard J Martin, Sasa M Trailovic, Alan P Robertson
Zolvix® is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs) in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes...
April 2018: International Journal for Parasitology, Drugs and Drug Resistance
Na Yu, Yang Liu, Xuan Wang, Jian Li, Haibo Bao, Zewen Liu
Nicotinic acetylcholine receptor (nAChR) subunits are encoded by a large multigene family and generate a large number of pentameric receptors with various properties. At present, nematode species, such as Caenorhabditis elegans, have the largest number of nAChR subunits. In this study, two nAChR subunits (Bxy-Unc-38 and Bxy-Unc-29) were cloned from Bursaphelenchus xylophilus, a fatal nematode pest on pine trees causing pine wilt disease. When Bxy-Unc-38 and Bxy-Unc-29 were co-expressed in Xenopus oocytes, constructed functional nAChRs showed agonist responses to acetylcholine and imidacloprid, a neonicotinoid insecticide...
November 2017: Pesticide Biochemistry and Physiology
Manish Rauthan, Jianke Gong, Jinzhi Liu, Zhaoyu Li, Seth A Wescott, Jianfeng Liu, X Z Shawn Xu
Chronic exposure to nicotine upregulates nicotinic acetylcholine receptors (nAChRs), and such upregulation is critical for the development of nicotine dependence in humans and animal models. However, how nicotine upregulates nAChRs is not well understood. Here, we identify a key role for microRNA in regulating nicotine-dependent behavior by modulating nAChR expression in C. elegans. We show that the nAChR gene acr-19 and alg-1, a key Argonaute-family member in the microRNA machinery, are specifically required for nicotine withdrawal response following chronic nicotine treatment...
November 7, 2017: Cell Reports
Shalini Trivedi, Priyanka Maurya, Shreesh Raj Sammi, Madan Mohan Gupta, Rakesh Pandey
Cholinergic function is compromised in plethora of neurodegenerative disorders especially Alzheimer's disease. Increasing acetylcholine (ACh) levels has been the mainstay in majority of the therapeutic regimens, accepted for management of disease. The present study investigates the efficacy of 5-Desmethylnobiletin (DN), a polymethoxyflavone in augmenting cholinergic function using Caenorhabditis elegans as a model organism. The studies revealed significant elevation in cholinergic transmission mediated through increased levels of ACh and activity of nicotinic acetylcholine receptors (nAChR)...
August 3, 2017: Neuroscience Letters
Hannah Hopewell, Kieran G Floyd, Daniel Burnell, John T Hancock, Joel Allainguillaume, Michael R Ladomery, Ian D Wilson
This study investigated the neurological effects of residual ground-water levels of thiacloprid on the non-target organism Caenorhabditis elegans. Nematodes treated with thiacloprid showed a dose-dependent and significantly increased twitch response at concentrations above 50 ng mL-1 that disabled their forward locomotion in liquid culture. In comparison with untreated controls, 10 ng mL-1 thiacloprid perturbed the chemosensory ability of C. elegans such that the nematodes no longer demonstrated positive chemotaxis towards a NaCl chemo-attractant, reducing their chemotaxis index from +0...
September 2017: Ecotoxicology
Saurabh Verma, Sudhanva Srinivas Kashyap, Alan Patrick Robertson, Richard John Martin
Many techniques for studying functional genomics of important target sites of anthelmintics have been restricted to Caenorhabditis elegans because they have failed when applied to animal parasites. To overcome these limitations, we have focused our research on the human nematode parasite Brugia malayi, which causes elephantiasis. Here, we combine single-cell PCR, whole muscle cell patch clamp, motility phenotyping (Worminator), and dsRNA for RNAi for functional genomic studies that have revealed, in vivo, four different muscle nAChRs ( M-, L-, P-, and N- )...
May 23, 2017: Proceedings of the National Academy of Sciences of the United States of America
Xin Huang, Hao Chen, Paul L Shaffer
Ivermectin acts as a positive allosteric modulator of several Cys-loop receptors including the glutamate-gated chloride channels (GluCls), γ-aminobutyric acid receptors (GABAARs), glycine receptors (GlyRs), and neuronal α7-nicotinic receptors (α7 nAChRs). The crystal structure of Caenorhabditis elegans GluCl complexed with ivermectin revealed the details of its ivermectin binding site. Although the electron microscopy structure of zebrafish GlyRα1 complexed with ivermectin demonstrated a similar binding orientation, detailed structural information on the ivermectin binding and pore opening for Cys-loop receptors in vertebrates has been elusive...
June 6, 2017: Structure
Robert Sobkowiak, Andrzej Zielezinski, Wojciech M Karlowski, Andrzej Lesicki
Nicotine may affect cell function by rearranging protein complexes. We aimed to determine nicotine-induced alterations of protein complexes in Caenorhabditis elegans (C. elegans) cells, thereby revealing links between nicotine exposure and protein complex modulation. We compared the proteomic alterations induced by low and high nicotine concentrations (0.01 mM and 1 mM) with the control (no nicotine) in vivo by using mass spectrometry (MS)-based techniques, specifically the cetyltrimethylammonium bromide (CTAB) discontinuous gel electrophoresis coupled with liquid chromatography (LC)-MS/MS and spectral counting...
January 3, 2017: Drug and Chemical Toxicology
Gracia Safdie, Jana F Liewald, Sarah Kagan, Emil Battat, Alexander Gottschalk, Millet Treinin
Brain function depends on a delicate balance between excitation and inhibition. Similarly, Caenorhabditis elegans motor system function depends on a precise balance between excitation and inhibition, as C. elegans muscles receive both inhibitory, GABAergic and excitatory, cholinergic inputs from motor neurons. Here we show that phosphorylation of the ER-resident chaperone of nicotinic acetylcholine receptors, RIC-3, leads to increased muscle excitability. RIC-3 phosphorylation at Ser-164 depends on opposing functions of the phosphatase calcineurin (TAX-6), and of the casein kinase II homologue KIN-10...
October 1, 2016: Molecular Biology of the Cell
Arunas Damijonaitis, Johannes Broichhagen, Tatsuya Urushima, Katharina Hüll, Jatin Nagpal, Laura Laprell, Matthias Schönberger, David H Woodmansee, Amir Rafiq, Martin P Sumser, Wolfgang Kummer, Alexander Gottschalk, Dirk Trauner
Nicotinic acetylcholine receptors (nAChRs) are essential for cellular communication in higher organisms. Even though a vast pharmacological toolset to study cholinergic systems has been developed, control of endogenous neuronal nAChRs with high spatiotemporal precision has been lacking. To address this issue, we have generated photoswitchable nAChR agonists and re-evaluated the known photochromic ligand, BisQ. Using electrophysiology, we found that one of our new compounds, AzoCholine, is an excellent photoswitchable agonist for neuronal α7 nAChRs, whereas BisQ was confirmed to be an agonist for the muscle-type nAChR...
May 20, 2015: ACS Chemical Neuroscience
Alan P Robertson, Sreekanth Puttachary, Samuel K Buxton, Richard J Martin
The cholinergic class of anthelmintic drugs is used for the control of parasitic nematodes. One of this class of drugs, tribendimidine (a symmetrical diamidine derivative, of amidantel), was developed in China for use in humans in the mid-1980s. It has a broader-spectrum anthelmintic action against soil-transmitted helminthiasis than other cholinergic anthelmintics, and is effective against hookworm, pinworms, roundworms, and Strongyloides and flatworm of humans. Although molecular studies on C. elegans suggest that tribendimidine is a cholinergic agonist that is selective for the same nematode muscle nAChR as levamisole, no direct electrophysiological observations in nematode parasites have been made to test this hypothesis...
February 2015: PLoS Neglected Tropical Diseases
Joseph R Polli, Dorothy L Dobbins, Robert A Kobet, Mary A Farwell, Baohong Zhang, Myon-Hee Lee, Xiaoping Pan
Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans' (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine-induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine-induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software...
March 2015: Neurotoxicology
Edward G Hawkins, Ian Martin, Lindsay M Kondo, Meredith E Judy, Victoria E Brings, Chung-Lung Chan, GinaMari G Blackwell, Jill C Bettinger, Andrew G Davies
Understanding the genes and mechanisms involved in acute alcohol responses has the potential to allow us to predict an individual's predisposition to developing an alcohol use disorder. To better understand the molecular pathways involved in the activating effects of alcohol and the acute functional tolerance that can develop to such effects, we characterized a novel ethanol-induced hypercontraction response displayed by Caenorhabditis elegans. We compared body size of animals prior to and during ethanol treatment and showed that acute exposure to ethanol produced a concentration-dependent decrease in size followed by recovery to their untreated size by 40 min despite continuous treatment...
January 2015: Genetics
Emiliano Cohen, Marios Chatzigeorgiou, Steven J Husson, Wagner Steuer-Costa, Alexander Gottschalk, William R Schafer, Millet Treinin
Polymodal nociceptors sense and integrate information on injurious mechanical, thermal, and chemical stimuli. Chemical signals either activate nociceptors or modulate their responses to other stimuli. One chemical known to activate or modulate responses of nociceptors is acetylcholine (ACh). Across evolution nociceptors express subunits of the nicotinic acetylcholine receptor (nAChR) family, a family of ACh-gated ion channels. The roles of ACh and nAChRs in nociceptor function are, however, poorly understood...
March 2014: Molecular and Cellular Neurosciences
Kristin Lees, Andrew K Jones, Kazuhiko Matsuda, Miki Akamatsu, David B Sattelle, Debra J Woods, Alan S Bowman
Ticks and tick-borne diseases have a major impact on human and animal health worldwide. Current control strategies rely heavily on the use of chemical acaricides, most of which target the CNS and with increasing resistance, new drugs are urgently needed. Nicotinic acetylcholine receptors (nAChRs) are targets of highly successful insecticides. We isolated a full-length nAChR α subunit from a normalised cDNA library from the synganglion (brain) of the brown dog tick, Rhipicephalus sanguineus. Phylogenetic analysis has shown this R...
January 2014: International Journal for Parasitology
Nelli Mnatsakanyan, Michaela Jansen
Nicotinic acetylcholine receptors (nAChR) are members of the Cys-loop ligand-gated ion channel superfamily. Muscle nAChR are heteropentamers that assemble from two α, and one each of β, γ, and δ subunits. Each subunit is composed of three domains, extracellular, transmembrane and intracellular. The transmembrane domain consists of four α-helical segments (M1-M4). Pioneering structural information was obtained using electronmicroscopy of Torpedo nAChR. The recently solved X-ray structure of the first eukaryotic Cys-loop receptor, a truncated (intracellular domain missing) glutamate-gated chloride channel α (GluClα) showed the same overall architecture...
June 2013: Journal of Neurochemistry
Lindy Holden-Dye, Michelle Joyner, Vincent O'Connor, Robert J Walker
Nicotinic acetylcholine receptors (nAChRs) play a key role in the normal physiology of nematodes and provide an established target site for anthelmintics. The free-living nematode, Caenorhabditis elegans, has a large number of nAChR subunit genes in its genome and so provides an experimental model for testing novel anthelmintics which act at these sites. However, many parasitic nematodes lack specific genes present in C. elegans, and so care is required in extrapolating from studies using C. elegans to the situation in other nematodes...
December 2013: Parasitology International
Taixiang Saur, Sarah E DeMarco, Angelica Ortiz, Gregory R Sliwoski, Limin Hao, Xin Wang, Bruce M Cohen, Edgar A Buttner
We report a genome-wide RNA interference (RNAi) screen for Suppressors of Clozapine-induced Larval Arrest (scla genes) in Caenorhabditis elegans, the first genetic suppressor screen for antipsychotic drug (APD) targets in an animal. The screen identifies 40 suppressors, including the α-like nicotinic acetylcholine receptor (nAChR) homolog acr-7. We validate the requirement for acr-7 by showing that acr-7 knockout suppresses clozapine-induced larval arrest and that expression of a full-length translational GFP fusion construct rescues this phenotype...
2013: PLoS Genetics
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