title: Distinct roles of the DmNav and DSC1 channels in the action of DDT and pyrethroids.
abstract: Voltage-gated sodium channels (Nav channels) are critical for electrical signaling in the nervous system and are the primary targets of the insecticides DDT and pyrethroids. In Drosophila melanogaster, besides the canonical Nav channel, Para (also called DmNav), there is a sodium channel-like cation channel called DSC1 (Drosophila sodium channel 1). Temperature-sensitive paralytic mutations in DmNav (para(ts)) confer resistance to DDT and pyrethroids, whereas DSC1 knockout flies exhibit enhanced sensitivity to pyrethroids. To further define the roles and interaction of DmNav and DSC1 channels in DDT and pyrethroid neurotoxicology, we generated a DmNav/DSC1 double mutant line by introducing a para(ts1) allele (carrying the I265N mutation) into a DSC1 knockout line. We confirmed that the I265N mutation reduced the sensitivity to two pyrethroids, permethrin and deltamethrin of a DmNav variant expressed in Xenopus oocytes. Computer modeling predicts that the I265N mutation confers pyrethroid resistance by allosterically altering the second pyrethroid receptor site on the DmNav channel. Furthermore, we found that I265N-mediated pyrethroid resistance in para(ts1) mutant flies was almost completely abolished in para(ts1);DSC1(-/-) double mutant flies. Unexpectedly, however, the DSC1 knockout flies were less sensitive to DDT, compared to the control flies (w(1118A)), and the para(ts1);DSC1(-/-) double mutant flies were even more resistant to DDT compared to the DSC1 knockout or para(ts1) mutant. Our findings revealed distinct roles of the DmNav and DSC1 channels in the neurotoxicology of DDT vs. pyrethroids and implicate the exciting possibility of using DSC1 channel blockers or modifiers in the management of pyrethroid resistance.
authors: Department of Entomology, Michigan State University, East Lansing, MI 48824, United States.
authors: Frank D
authors: FD
authors: Rinkevich
authors: Department of Entomology, Michigan State University, East Lansing, MI 48824, United States.
authors: Yuzhe
authors: Y
authors: Du
authors: Department of Entomology, Michigan State University, East Lansing, MI 48824, United States.
authors: Josh
authors: J
authors: Tolinski
authors: Department of Biology, University of Iowa, Iowa City, IA 52242, United States.
authors: Atsushi
authors: A
authors: Ueda
authors: Department of Biology, University of Iowa, Iowa City, IA 52242, United States.
authors: Chun-Fang
authors: CF
authors: Wu
authors: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Sechenov Institute of Evolutionary Physiology & Biochemistry, Russian Academy of Sciences, St. Petersburg, Russian Federation.
authors: Boris S
authors: BS
authors: Zhorov
authors: Department of Entomology, Michigan State University, East Lansing, MI 48824, United States. Electronic address: dongk@msu.edu.
authors: Ke
authors: K
authors: Dong
mesh_terms: D000818:Animals; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D003634:DDT / Q000633:toxicity*; D029721:Drosophila Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D007306:Insecticides / Q000633:toxicity*; D009154:Mutation; D009865:Oocytes; D011722:Pyrethrins / Q000633:toxicity*; D015222:Sodium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus
chemical_list: D015220:Calcium Channels; D029721:Drosophila Proteins; D007306:Insecticides; C581616:NaCP60E protein, Drosophila; D011722:Pyrethrins; D015222:Sodium Channels; C469950:para protein, Drosophila; D003634:DDT
keywords: DDT; DSC1; Pyrethroids insecticide resistance; Voltage-gated sodium channel