{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T11:58:42Z","timestamp":1790078322196,"version":"4.0.1"},"reference-count":48,"publisher":"The Company of Biologists","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,5,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The use of insecticide-treated nets and indoor residual insecticides targeting adult mosquito vectors is a key element in malaria control programs. However, mosquito resistance to the insecticides used in these applications threatens malaria control efforts. Recently, the mass drug administration of ivermectin (IVM) has been shown to kill Anopheles gambiae mosquitoes and disrupt Plasmodium falciparum transmission in the field. We cloned the molecular target of IVM from A. gambiae, the glutamate-gated chloride channel (AgGluCl), and characterized its transcriptional patterns, protein expression and functional responses to glutamate and IVM. AgGluCl cloning revealed an unpredicted fourth splice isoform as well as a novel exon and splice site. The predicted gene products contained heterogeneity in the N-terminal extracellular domain and the intracellular loop region. Responses to glutamate and IVM were measured using two-electrode voltage clamp on Xenopus laevis oocytes expressing AgGluCl. IVM induced non-persistent currents in AgGluCl-a1 and did not potentiate glutamate responses. In contrast, AgGluCl-b was insensitive to IVM, suggesting that the AgGluCl gene could produce IVM-sensitive and -insensitive homomultimers from alternative splicing. AgGluCl isoform-specific transcripts were measured across tissues, ages, blood feeding status and sex, and were found to be differentially transcribed across these physiological variables. Lastly, we stained adult, female A. gambiae for GluCl expression. The channel was expressed in the antenna, Johnston's organ, supraesophageal ganglion and thoracic ganglia. In summary, we have characterized the first GluCl from a mosquito, A. gambiae, and described its unique activity and expression with respect to it as the target of the insecticide IVM.<\/jats:p>","DOI":"10.1242\/jeb.118570","type":"journal-article","created":{"date-parts":[[2015,5,20]],"date-time":"2015-05-20T17:19:22Z","timestamp":1432142362000},"page":"1478-1486","source":"Crossref","is-referenced-by-count":84,"title":["Characterization of the target of ivermectin, the glutamate-gated chloride channel, from\n                    <i>Anopheles gambiae<\/i>"],"prefix":"10.1242","volume":"218","author":[{"given":"Jacob I.","family":"Meyers","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523-1617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meg","family":"Gray","sequence":"additional","affiliation":[{"name":"Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, 1692 Campus Delivery, Fort Collins, CO 80523-1692, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wojtek","family":"Kuklinski","sequence":"additional","affiliation":[{"name":"Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, 1692 Campus Delivery, Fort Collins, CO 80523-1692, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas B.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Colorado State University, 1370 Campus Delivery, Fort Collins, CO 80523-1370, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher D.","family":"Snow","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biological Engineering, Colorado State University, 1370 Campus Delivery, Fort Collins, CO 80523-1370, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"IV","given":"William C.","family":"Black","sequence":"additional","affiliation":[{"name":"Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, 1692 Campus Delivery, Fort Collins, CO 80523-1692, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn M.","family":"Partin","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Colorado State University, 1617 Campus Delivery, Fort Collins, CO 80523-1617, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian D.","family":"Foy","sequence":"additional","affiliation":[{"name":"Arthropod-borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, 1692 Campus Delivery, Fort Collins, CO 80523-1692, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","reference":[{"key":"2021042422575756000_JEB118570C1","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1186\/1475-2875-13-417","article-title":"Evaluation of ivermectin mass drug administration for malaria transmission control across different West African environments","volume":"13","author":"Alout","year":"2014","journal-title":"Malar. J."},{"key":"2021042422575756000_JEB118570C2","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/S0092-8674(04)00173-4","article-title":"Complement-like protein TEP1 is a determinant of vectorial capacity in the malaria vector Anopheles gambiae","volume":"116","author":"Blandin","year":"2004","journal-title":"Cell"},{"key":"2021042422575756000_JEB118570C3","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1006\/jmbi.1999.3310","article-title":"Sequence and structure-based prediction of eukaryotic protein phosphorylation sites","volume":"294","author":"Blom","year":"1999","journal-title":"J. Mol. Biol."},{"key":"2021042422575756000_JEB118570C4","doi-asserted-by":"publisher","first-page":"3006","DOI":"10.1242\/jeb.106708","article-title":"Hemolymph circulation in insect sensory appendages: functional mechanics of antennal accessory pulsatile organs (auxiliary hearts) in the mosquito Anopheles gambiae","volume":"217","author":"Boppana","year":"2014","journal-title":"J. Exp. Biol."},{"key":"2021042422575756000_JEB118570C5","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1146\/annurev.en.36.010191.001035","article-title":"The sensory physiology of host-seeking behavior in mosquitoes","volume":"36","author":"Bowen","year":"1991","journal-title":"Annu. Rev. Entomol."},{"key":"2021042422575756000_JEB118570C6","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1016\/j.vetpar.2011.10.006","article-title":"Pharmacological characterization of the Haemonchus contortus GABA-gated chloride channel, Hco-UNC-49: modulation by macrocyclic lactone anthelmintics and a receptor for piperazine","volume":"185","author":"Brown","year":"2012","journal-title":"Vet. Parasitol."},{"key":"2021042422575756000_JEB118570C7","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.actatropica.2011.10.007","article-title":"Comparative evaluation of systemic drugs for their effects against Anopheles gambiae","volume":"121","author":"Butters","year":"2012","journal-title":"Acta Trop."},{"key":"2021042422575756000_JEB118570C8","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1038\/371707a0","article-title":"Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans","volume":"371","author":"Cully","year":"1994","journal-title":"Nature"},{"key":"2021042422575756000_JEB118570C9","doi-asserted-by":"publisher","first-page":"20187","DOI":"10.1074\/jbc.271.33.20187","article-title":"Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin","volume":"271","author":"Cully","year":"1996","journal-title":"J. Biol. Chem."},{"key":"2021042422575756000_JEB118570C10","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1006\/jmbi.1993.1170","article-title":"Backbone-dependent rotamer library for proteins Application to side-chain prediction","volume":"230","author":"Dunbrack","year":"1993","journal-title":"J. Mol. Biol."},{"key":"2021042422575756000_JEB118570C11","doi-asserted-by":"publisher","DOI":"10.1002\/0471140864.ps0209s50","article-title":"Comparative protein structure modeling using MODELLER","author":"Eswar","year":"2007","journal-title":"Curr. Protoc. Protein Sci."},{"key":"2021042422575756000_JEB118570C12","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1007\/BF00318153","article-title":"The optic lobe projection pattern of polarization-sensitive photoreceptor cells in Drosophila melanogaster","volume":"265","author":"Fortini","year":"1991","journal-title":"Cell Tissue Res."},{"key":"2021042422575756000_JEB118570C13","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1124\/mol.114.095869","article-title":"Exon 3 splicing and mutagenesis identify residues influencing cell surface density of heterologously expressed silkworm (Bombyx mori) glutamate-gated chloride channels","volume":"86","author":"Furutani","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"2021042422575756000_JEB118570C14","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1242\/jeb.205.9.1199","article-title":"The mechanical basis of Drosophila audition","volume":"205","author":"Gopfert","year":"2002","journal-title":"J. Exp. Biol."},{"key":"2021042422575756000_JEB118570C15","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1038\/nature10139","article-title":"Principles of activation and permeation in an anion-selective Cys-loop receptor","volume":"474","author":"Hibbs","year":"2011","journal-title":"Nature"},{"key":"2021042422575756000_JEB118570C16","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1002\/cne.20691","article-title":"Projection patterns of gustatory neurons in the suboesophageal ganglion and tritocerebrum of mosquitoes","volume":"492","author":"Ignell","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"2021042422575756000_JEB118570C17","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1002\/cne.20800","article-title":"Neuronal architecture of the mosquito deutocerebrum","volume":"493","author":"Ignell","year":"2005","journal-title":"J. Comp. Neurol."},{"key":"2021042422575756000_JEB118570C18","doi-asserted-by":"publisher","first-page":"2700","DOI":"10.1073\/pnas.79.8.2700","article-title":"Antibodies to horseradish peroxidase as specific neuronal markers in Drosophila and in grasshopper embryos","volume":"79","author":"Jan","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042422575756000_JEB118570C19","doi-asserted-by":"publisher","first-page":"2642","DOI":"10.1152\/jn.01234.2006","article-title":"Dorsal unpaired median neurons of Locusta migratoria express ivermectin- and fipronil-sensitive glutamate-gated chloride channels","volume":"97","author":"Janssen","year":"2007","journal-title":"J. Neurophysiol."},{"key":"2021042422575756000_JEB118570C20","doi-asserted-by":"publisher","first-page":"2587","DOI":"10.1152\/jn.00466.2009","article-title":"Cys-loop ligand-gated chloride channels in dorsal unpaired median neurons of Locusta migratoria","volume":"103","author":"Janssen","year":"2010","journal-title":"J. Neurophysiol."},{"key":"2021042422575756000_JEB118570C21","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s10158-009-0089-7","article-title":"Alternative splicing of the Anopheles gambiae nicotinic acetylcholine receptor, Agamalphabeta9, generates both alpha and beta subunits","volume":"9","author":"Jones","year":"2009","journal-title":"Invert. Neurosci."},{"key":"2021042422575756000_JEB118570C22","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1016\/j.jinsphys.2013.06.005","article-title":"Differential distribution of glutamate- and GABA-gated chloride channels in the housefly Musca domestica","volume":"59","author":"Kita","year":"2013","journal-title":"J. Insect Physiol."},{"key":"2021042422575756000_JEB118570C23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ibmb.2013.11.004","article-title":"Expression pattern and function of alternative splice variants of glutamate-gated chloride channel in the housefly Musca domestica","volume":"45","author":"Kita","year":"2014","journal-title":"Insect Biochem. Mol. Biol."},{"key":"2021042422575756000_JEB118570C24","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.actatropica.2010.06.001","article-title":"The effect of oral anthelmintics on the survivorship and re-feeding frequency of anthropophilic mosquito disease vectors","volume":"116","author":"Kobylinski","year":"2010","journal-title":"Acta Trop."},{"key":"2021042422575756000_JEB118570C25","doi-asserted-by":"publisher","first-page":"3","DOI":"10.4269\/ajtmh.2011.11-0160","article-title":"Ivermectin mass drug administration to humans disrupts malaria parasite transmission in Senegalese villages","volume":"85","author":"Kobylinski","year":"2011","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"2021042422575756000_JEB118570C26","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1186\/1475-2875-11-381","article-title":"Ivermectin inhibits the sporogony of Plasmodium falciparum in Anopheles gambiae","volume":"11","author":"Kobylinski","year":"2012","journal-title":"Malar. J."},{"key":"2021042422575756000_JEB118570C27","doi-asserted-by":"publisher","first-page":"10294","DOI":"10.1073\/pnas.1220560110","article-title":"Glutamate is an inhibitory neurotransmitter in the Drosophila olfactory system","volume":"110","author":"Liu","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042422575756000_JEB118570C28","doi-asserted-by":"publisher","first-page":"999","DOI":"10.1002\/jcc.21204","article-title":"SHARPEN-systematic hierarchical algorithms for rotamers and proteins on an extended network","volume":"30","author":"Loksha","year":"2009","journal-title":"J. Comput. Chem."},{"key":"2021042422575756000_JEB118570C29","doi-asserted-by":"publisher","first-page":"60","DOI":"10.3389\/fnmol.2012.00060","article-title":"Molecular mechanisms of Cys-loop ion channel receptor modulation by ivermectin","volume":"5","author":"Lynagh","year":"2012","journal-title":"Front. Mol. Neurosci."},{"key":"2021042422575756000_JEB118570C30","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1016\/j.tips.2012.05.002","article-title":"Ivermectin binding sites in human and invertebrate Cys-loop receptors","volume":"33","author":"Lynagh","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"2021042422575756000_JEB118570C31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2583.2006.00610.x","article-title":"Genome-wide analysis of gene expression in adult Anopheles gambiae","volume":"15","author":"Marinotti","year":"2006","journal-title":"Insect Mol. Biol."},{"key":"2021042422575756000_JEB118570C32","doi-asserted-by":"publisher","first-page":"8181","DOI":"10.1523\/JNEUROSCI.2017-10.2011","article-title":"Synchronized bilateral synaptic inputs to Drosophila melanogaster neuropeptidergic rest\/arousal neurons","volume":"31","author":"McCarthy","year":"2011","journal-title":"J. Neurosci."},{"key":"2021042422575756000_JEB118570C33","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1124\/mol.108.053363","article-title":"An ivermectin-sensitive glutamate-gated chloride channel from the parasitic nematode Haemonchus contortus","volume":"75","author":"McCavera","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"2021042422575756000_JEB118570C34","doi-asserted-by":"publisher","first-page":"e35563","DOI":"10.1371\/journal.pone.0035563","article-title":"Length and amino acid sequence of peptides substituted for the 5-HT3A receptor M3M4 loop may affect channel expression and desensitization","volume":"7","author":"McKinnon","year":"2012","journal-title":"PLoS ONE"},{"key":"2021042422575756000_JEB118570C35","doi-asserted-by":"publisher","first-page":"D729","DOI":"10.1093\/nar\/gkr1089","article-title":"VectorBase: improvements to a bioinformatics resource for invertebrate vector genomics","volume":"40","author":"Megy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2021042422575756000_JEB118570C36","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1242\/jeb.118596","article-title":"Mosquitocidal properties of IgG targeting the glutamate-gated chloride channel in three mosquito disease vectors (Diptera: Culicidae)","volume":"218","author":"Meyers","year":"2015","journal-title":"J. Exp. Biol."},{"key":"2021042422575756000_JEB118570C37","doi-asserted-by":"publisher","first-page":"20120","DOI":"10.1073\/pnas.1011983107","article-title":"Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi","volume":"107","author":"Moreno","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042422575756000_JEB118570C38","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ijantimicag.2007.08.023","article-title":"Ivermectin: 25 years and still going strong","volume":"31","author":"\u00d5mura","year":"2008","journal-title":"Int. J. Antimicrob. Agents"},{"key":"2021042422575756000_JEB118570C39","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1093\/cid\/ciu797","article-title":"Efficacy and safety of the mosquitocidal drug ivermectin to prevent malaria transmission after treatment: a double-blind, randomized, clinical trial","volume":"60","author":"Ouedraogo","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"2021042422575756000_JEB118570C40","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1523\/JNEUROSCI.21-06-01939.2001","article-title":"Domain interactions regulating AMPA receptor desensitization","volume":"21","author":"Partin","year":"2001","journal-title":"J. Neurosci."},{"key":"2021042422575756000_JEB118570C41","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.pt.2010.08.004","article-title":"Pyrethroid resistance in African Anopheline mosquitoes: what are the implications for malaria control?","volume":"27","author":"Ranson","year":"2011","journal-title":"Trends Parasitol."},{"key":"2021042422575756000_JEB118570C42","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1152\/jn.2002.88.2.847","article-title":"Electrophysiological analysis of synaptic transmission in central neurons of Drosophila larvae","volume":"88","author":"Rohrbough","year":"2002","journal-title":"J. Neurophysiol."},{"key":"2021042422575756000_JEB118570C43","doi-asserted-by":"publisher","first-page":"16254","DOI":"10.1074\/jbc.M411759200","article-title":"A novel chloride channel in Drosophila melanogaster is inhibited by protons","volume":"280","author":"Schnizler","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021042422575756000_JEB118570C44","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1186\/1475-2875-9-365","article-title":"Mass drug administration of ivermectin in south-eastern Senegal reduces the survivorship of wild-caught, blood fed malaria vectors","volume":"9","author":"Sylla","year":"2010","journal-title":"Malar. J."},{"key":"2021042422575756000_JEB118570C45","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1016\/S1473-3099(11)70194-3","article-title":"Malaria morbidity and pyrethroid resistance after the introduction of insecticide-treated bednets and artemisinin-based combination therapies: a longitudinal study","volume":"11","author":"Trape","year":"2011","journal-title":"Lancet Infect. Dis."},{"key":"2021042422575756000_JEB118570C46","doi-asserted-by":"publisher","first-page":"734","DOI":"10.1111\/j.1471-4159.2010.07060.x","article-title":"Assembly of nicotinic and other Cys-loop receptors","volume":"116","author":"Tsetlin","year":"2011","journal-title":"J. Neurochem."},{"key":"2021042422575756000_JEB118570C47","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1016\/j.neuro.2004.04.004","article-title":"Kinetic and pharmacological characterization of desensitizing and non-desensitizing glutamate-gated chloride channels in cockroach neurons","volume":"25","author":"Zhao","year":"2004","journal-title":"Neurotoxicology"},{"key":"2021042422575756000_JEB118570C48","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.1074\/jbc.M107635200","article-title":"Identification of two novel Drosophila melanogaster histamine-gated chloride channel subunits expressed in the eye","volume":"277","author":"Zheng","year":"2002","journal-title":"J. Biol. Chem."}],"container-title":["Journal of Experimental Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/jeb\/article-pdf\/218\/10\/1478\/1886153\/jeb118570.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/jeb\/article-pdf\/218\/10\/1478\/1886153\/jeb118570.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T14:30:22Z","timestamp":1652020222000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/jeb\/article\/218\/10\/1478\/774\/Characterization-of-the-target-of-ivermectin-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,5,15]]},"references-count":48,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2015,5,15]]}},"URL":"https:\/\/doi.org\/10.1242\/jeb.118570","relation":{},"ISSN":["1477-9145","0022-0949"],"issn-type":[{"value":"1477-9145","type":"electronic"},{"value":"0022-0949","type":"print"}],"subject":[],"published":{"date-parts":[[2015,5,15]]}}}