Du Y , Nomura Y , Zhorov BS , Dong K .

R01 GM057440 NIGMS NIH HHS

	Figure 1. The topology of the mosquito sodium channel indicating the structural features that are critical for sodium channel function. The sodium channel protein contains four homologous repeat domains (I–IV), each having six α-helical transmembrane segments (S1–S6). In each domain, the S1–S4 segments constitute the voltage-sensing module. “+” represent positively charged amino acid residue in S4 segment. The segments S5, S6, and membrane-reentrant P-loops that connect the S5 and S6 segments form the pore module (fill in gray). The amino acids D, E, K, and A (the selectivity-filter motif “DEKA”) in the analogous positions of domains I, II, III, and IV, respectively, determine the ion selectivity of sodium channels. The isoleucine in the IFM (amino acid residues I, F and M) motif that is critical for fast inactivation in mammalian sodium channels is substituted with a methionine in insect sodium channels.
	Figure 2. Mutations in the sodium channel protein that are associated with pyrethroid resistance in Aedes aegypti. Solid circles denote the mutations that have been functionally confirmed in Xenopus oocytes, half-solid circles indicate one of the substitutions has been confirmed in oocytes, and empty circles indicate the mutations that have not been confirmed or examined in oocytes. Amino acid positions of mutations are numbered based on the house fly sodium channel protein, Vssc1 (Genbank accession number: AAB47604). The numbers of the corresponding positions in AaNav (Genbank accession number: EU399181) are indicated in parenthesis.
	Figure 3. The pore-domain model of the mosquito sodium channel. (A, B), Side views; (C) Extracellular view; (D) Intracellular view. Helical segments of the channel protein in domains I, II, III, and IV are shown as yellow, red, green, and gray cylinders, respectively. Location of the pyrethroid receptor sites PyR1 and PyR2 is indicated by the magenta and blue circles, respectively. The four positions where three kdr mutations are detected in the mosquito sodium channel and another kdr mutation (L1014F) in other insect sodium channels are shown as space-filled side chains of the wild-type residues. Only carbon atoms (gray spheres) in these side chains are shown, whereas the hydrogen atoms are removed for clarity. Note that opposite faces of helix IIS6 contain residues that contribute to PyR1 (V1016) or PyR2 (I1011 and L1014).

Alvarez, Frequency of V1016I and F1534C mutations in the voltage-gated sodium channel gene in Aedes aegypti in Venezuela. 2015, Pubmed

Alvarez, Frequency of V1016I and F1534C mutations in the voltage-gated sodium channel gene in Aedes aegypti in Venezuela. 2015, Pubmed
Bona, Larval application of sodium channel homologous dsRNA restores pyrethroid insecticide susceptibility in a resistant adult mosquito population. 2016, Pubmed
Brengues, Pyrethroid and DDT cross-resistance in Aedes aegypti is correlated with novel mutations in the voltage-gated sodium channel gene. 2003, Pubmed
Catterall, Structure and function of voltage-gated sodium channels at atomic resolution. 2014, Pubmed
Chang, A novel amino acid substitution in a voltage-gated sodium channel is associated with knockdown resistance to permethrin in Aedes aegypti. 2009, Pubmed
Chapadense, Phenotypic and genotypic profile of pyrethroid resistance in populations of the mosquito Aedes aegypti from Goiânia, Central West Brazil. 2015, Pubmed
Chen, First identification of kdr allele F1534S in VGSC gene and its association with resistance to pyrethroid insecticides in Aedes albopictus populations from Haikou City, Hainan Island, China. 2016, Pubmed
Chen, Molecular ecology of pyrethroid knockdown resistance in Culex pipiens pallens mosquitoes. 2010, Pubmed
Cornel, Surveillance, insecticide resistance and control of an invasive Aedes aegypti (Diptera: Culicidae) population in California. 2016, Pubmed
Cornel, Surveillance, insecticide resistance and control of an invasive Aedes aegypti (Diptera: Culicidae) population in California. 2016, Pubmed
Dong, A single amino acid change in the para sodium channel protein is associated with knockdown-resistance (kdr) to pyrethroid insecticides in German cockroach. 1997, Pubmed
Dong, Molecular biology of insect sodium channels and pyrethroid resistance. 2014, Pubmed
Du, Identification of a cluster of residues in transmembrane segment 6 of domain III of the cockroach sodium channel essential for the action of pyrethroid insecticides. 2009, Pubmed
Du, Rotational Symmetry of Two Pyrethroid Receptor Sites in the Mosquito Sodium Channel. 2015, Pubmed
Du, Evidence for Dual Binding Sites for 1,1,1-Trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) in Insect Sodium Channels. 2016, Pubmed
Du, Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel. 2013, Pubmed , Xenbase
Dusfour, Deltamethrin Resistance Mechanisms in Aedes aegypti Populations from Three French Overseas Territories Worldwide. 2015, Pubmed
Enayati, Molecular evidence for a kdr-like pyrethroid resistance mechanism in the malaria vector mosquito Anopheles stephensi. 2003, Pubmed
Harris, Pyrethroid resistance in Aedes aegypti from Grand Cayman. 2010, Pubmed
Head, Novel mutations in the para-homologous sodium channel gene associated with phenotypic expression of nerve insensitivity resistance to pyrethroids in Heliothine lepidoptera. 1998, Pubmed
Hirata, A single crossing-over event in voltage-sensitive Na+ channel genes may cause critical failure of dengue mosquito control by insecticides. 2014, Pubmed , Xenbase
Hodgdon, Determination of knockdown resistance allele frequencies in global human head louse populations using the serial invasive signal amplification reaction. 2010, Pubmed
Hu, A sodium channel mutation identified in Aedes aegypti selectively reduces cockroach sodium channel sensitivity to type I, but not type II pyrethroids. 2011, Pubmed , Xenbase
Ishak, Contrasting patterns of insecticide resistance and knockdown resistance (kdr) in the dengue vectors Aedes aegypti and Aedes albopictus from Malaysia. 2015, Pubmed
Jones, Footprints of positive selection associated with a mutation (N1575Y) in the voltage-gated sodium channel of Anopheles gambiae. 2012, Pubmed
Kasai, First detection of a putative knockdown resistance gene in major mosquito vector, Aedes albopictus. 2011, Pubmed
Kawada, Discovery of Point Mutations in the Voltage-Gated Sodium Channel from African Aedes aegypti Populations: Potential Phylogenetic Reasons for Gene Introgression. 2016, Pubmed
Kawada, Co-occurrence of point mutations in the voltage-gated sodium channel of pyrethroid-resistant Aedes aegypti populations in Myanmar. 2014, Pubmed
Kawada, Widespread distribution of a newly found point mutation in voltage-gated sodium channel in pyrethroid-resistant Aedes aegypti populations in Vietnam. 2009, Pubmed
Kushwah, Pyrethroid-resistance and presence of two knockdown resistance (kdr) mutations, F1534C and a novel mutation T1520I, in Indian Aedes aegypti. 2015, Pubmed
Lee, Mutations in the house fly Vssc1 sodium channel gene associated with super-kdr resistance abolish the pyrethroid sensitivity of Vssc1/tipE sodium channels expressed in Xenopus oocytes. 1999, Pubmed , Xenbase
Li, Relationship between insecticide resistance and kdr mutations in the dengue vector Aedes aegypti in Southern China. 2015, Pubmed
Linss, Distribution and dissemination of the Val1016Ile and Phe1534Cys Kdr mutations in Aedes aegypti Brazilian natural populations. 2014, Pubmed
Liu, Novel point mutations in the German cockroach para sodium channel gene are associated with knockdown resistance (kdr) to pyrethroid insecticides. 2000, Pubmed
Lol, Molecular evidence for historical presence of knock-down resistance in Anopheles albimanus, a key malaria vector in Latin America. 2013, Pubmed
Lüleyap, Detection of knockdown resistance mutations in Anopheles sacharovi (Diptera: Culicidae) and genetic distance with Anopheles gambiae (Diptera: Culicidae) using cDNA sequencing of the voltage-gated sodium channel gene. 2002, Pubmed
Marcombe, Insecticide resistance status of United States populations of Aedes albopictus and mechanisms involved. 2014, Pubmed
Martinez-Torres, Molecular characterization of pyrethroid knockdown resistance (kdr) in the major malaria vector Anopheles gambiae s.s. 1998, Pubmed
Miyazaki, Cloning and sequencing of the para-type sodium channel gene from susceptible and kdr-resistant German cockroaches (Blattella germanica) and house fly (Musca domestica). 1996, Pubmed
Narahashi, Ion channels as targets for insecticides. 1998, Pubmed
Narahashi, Neuronal ion channels as the target sites of insecticides. 1996, Pubmed
O'Reilly, Modelling insecticide-binding sites in the voltage-gated sodium channel. 2006, Pubmed
Pang, Low efficacy of delthamethrin-treated net against Singapore Aedes aegypti is associated with kdr-type resistance. 2015, Pubmed
Rajatileka, Development and application of a simple colorimetric assay reveals widespread distribution of sodium channel mutations in Thai populations of Aedes aegypti. 2008, Pubmed
Ranson, Insecticide Resistance in African Anopheles Mosquitoes: A Worsening Situation that Needs Urgent Action to Maintain Malaria Control. 2016, Pubmed
Ranson, Identification of a point mutation in the voltage-gated sodium channel gene of Kenyan Anopheles gambiae associated with resistance to DDT and pyrethroids. 2000, Pubmed
Rinkevich, Diversity and Convergence of Sodium Channel Mutations Involved in Resistance to Pyrethroids. 2013, Pubmed
Saavedra-Rodriguez, A mutation in the voltage-gated sodium channel gene associated with pyrethroid resistance in Latin American Aedes aegypti. 2007, Pubmed
Silver, Voltage-Gated Sodium Channels as Insecticide Targets. 2014, Pubmed
Singh, Presence of two alternative kdr-like mutations, L1014F and L1014S, and a novel mutation, V1010L, in the voltage gated Na+ channel of Anopheles culicifacies from Orissa, India. 2010, Pubmed
Smith, Pyrethroid resistance in Aedes aegypti and Aedes albopictus: Important mosquito vectors of human diseases. 2016, Pubmed
Soderlund, Neurotoxic actions of pyrethroid insecticides. 1989, Pubmed
Soderlund, Molecular mechanisms of pyrethroid insecticide neurotoxicity: recent advances. 2012, Pubmed
Srisawat, Field-collected permethrin-resistant Aedes aegypti from central Thailand contain point mutations in the domain IIS6 of the sodium channel gene (KDR). 2012, Pubmed
Stenhouse, Detection of the V1016G mutation in the voltage-gated sodium channel gene of Aedes aegypti (Diptera: Culicidae) by allele-specific PCR assay, and its distribution and effect on deltamethrin resistance in Thailand. 2013, Pubmed
Stump, Dynamics of the pyrethroid knockdown resistance allele in western Kenyan populations of Anopheles gambiae in response to insecticide-treated bed net trials. 2004, Pubmed
Tan, First detection of multiple knockdown resistance (kdr)-like mutations in voltage-gated sodium channel using three new genotyping methods in Anopheles sinensis from Guangxi Province, China. 2012, Pubmed
Usherwood, Mutations in DIIS5 and the DIIS4-S5 linker of Drosophila melanogaster sodium channel define binding domains for pyrethroids and DDT. 2007, Pubmed , Xenbase
Vais, Activation of Drosophila sodium channels promotes modification by deltamethrin. Reductions in affinity caused by knock-down resistance mutations. 2000, Pubmed , Xenbase
Vera-Maloof, Coevolution of the Ile1,016 and Cys1,534 Mutations in the Voltage Gated Sodium Channel Gene of Aedes aegypti in Mexico. 2015, Pubmed
Verhaeghen, Knockdown resistance in Anopheles vagus, An. sinensis, An. paraliae and An. peditaeniatus populations of the Mekong region. 2010, Pubmed
Wang, Detection and widespread distribution of sodium channel alleles characteristic of insecticide resistance in Culex pipiens complex mosquitoes in China. 2012, Pubmed
Williamson, Identification of mutations in the housefly para-type sodium channel gene associated with knockdown resistance (kdr) to pyrethroid insecticides. 1996, Pubmed
Wuliandari, Association between Three Mutations, F1565C, V1023G and S996P, in the Voltage-Sensitive Sodium Channel Gene and Knockdown Resistance in Aedes aegypti from Yogyakarta, Indonesia. 2015, Pubmed
Xu, Resistance in the mosquito, Culex quinquefasciatus, and possible mechanisms for resistance. 2005, Pubmed
Yanola, High-throughput assays for detection of the F1534C mutation in the voltage-gated sodium channel gene in permethrin-resistant Aedes aegypti and the distribution of this mutation throughout Thailand. 2011, Pubmed
Zhorov, Elucidation of pyrethroid and DDT receptor sites in the voltage-gated sodium channel. 2017, Pubmed