title: The Receptor Site and Mechanism of Action of Sodium Channel Blocker Insecticides.
abstract: Sodium channels are excellent targets of both natural and synthetic insecticides with high insect selectivity. Indoxacarb, its active metabolite DCJW, and metaflumizone (MFZ) belong to a relatively new class of sodium channel blocker insecticides (SCBIs) with a mode of action distinct from all other sodium channel-targeting insecticides, including pyrethroids. Electroneutral SCBIs preferably bind to and trap sodium channels in the inactivated state, a mechanism similar to that of cationic local anesthetics. Previous studies identified several SCBI-sensing residues that face the inner pore of sodium channels. However, the receptor site of SCBIs, their atomic mechanisms, and the cause of selective toxicity of MFZ remain elusive. Here, we have built a homology model of the open-state cockroach sodium channel BgNav1-1a. Our computations predicted that SCBIs bind in the inner pore, interact with a sodium ion at the focus of P1 helices, and extend their aromatic moiety into the III/IV domain interface (fenestration). Using model-driven mutagenesis and electrophysiology, we identified five new SCBI-sensing residues, including insect-specific residues. Our study proposes the first three-dimensional models of channel-bound SCBIs, sheds light on the molecular basis of MFZ selective toxicity, and suggests that a sodium ion located in the inner pore contributes to the receptor site for electroneutral SCBIs.
authors.affiliation: From the College of Plant Protection, Southwest University, Chongqing 400716, China, the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Yuzhe
authors.initials: Y
authors.lastname: Du
authors.affiliation: the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Dingxin
authors.initials: D
authors.lastname: Jiang
authors.affiliation: the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Caitlyn
authors.initials: C
authors.lastname: Behnke
authors.affiliation: the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Nomura
authors.affiliation: the Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario L8S 4K1, Canada, and the Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia zhorov@mcmaster.ca.
authors.forename: Boris S
authors.initials: BS
authors.lastname: Zhorov
authors.affiliation: the Department of Entomology, Genetics and Neuroscience Programs, Michigan State University, East Lansing, Michigan 48824, dongk@msu.edu.
authors.forename: Ke
authors.initials: K
authors.lastname: Dong
mesh_terms: D000818:Animals; D020048:Blattellidae / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007306:Insecticides / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000072417:Protein Domains; D012664:Semicarbazones / Q000737:chemistry / Q000494:pharmacology; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology
chemical_list: D019476:Insect Proteins; D007306:Insecticides; D062550:NAV1.1 Voltage-Gated Sodium Channel; D012664:Semicarbazones; D026941:Sodium Channel Blockers; C528570:metaflumizone
keywords: DCJW; computer modeling; electrophysiology; insect; ion channel; metaflumizone; molecular modeling; mutational analysis