Mutations in DIIS5 and the DIIS4–S5 linker of<i>Drosophila melanogaster</i>sodium channel define binding domains for pyrethroids and DDT

Usherwood, P.N.R.; Davies, T.G. Emyr; Mellor, Ian R.; O’Reilly, Andrias O.; Peng, Fang; Vais, Horia; Khambay, B. P. S.; Field, L. M.; Williamson, Martin S.

doi:10.1016/j.febslet.2007.10.057

Cited by 117 publications

(157 citation statements)

References 20 publications

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“…This model predicts that pyrethroids bind to the lipid-exposed interface formed by the linker helix connecting S4 and S5 in domain II (IIL45), and helices IIIS6 and IIS5 (the IIL45-IIS5-IIIS6 triangle model or site 1 hereinafter). Experimental data from systematic site-directed mutagenesis studies in these regions support this model (16,17). Several key kd mutations in IIL45, IIS5, and IIIS6 are predicted to confer resistance by altering pyrethroid binding (18,19).…”

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confidence: 65%

Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel

Nomura

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et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Pyrethroid insecticides are widely used as one of the most effective control measures in the global fight against agricultural arthropod pests and mosquito-borne diseases, including malaria and dengue. They exert toxic effects by altering the function of voltage-gated sodium channels, which are essential for proper electrical signaling in the nervous system. A major threat to the sustained use of pyrethroids for vector control is the emergence of mosquito resistance to pyrethroids worldwide. Here, we report the successful expression of a sodium channel, AaNa v 1-1, from Aedes aegypti in Xenopus oocytes, and the functional examination of nine sodium channel mutations that are associated with pyrethroid resistance in various Ae. aegypti and Anopheles gambiae populations around the world. Our analysis shows that five of the nine mutations reduce AaNa v 1-1 sensitivity to pyrethroids. Computer modeling and further mutational analysis revealed a surprising finding: Although two of the five confirmed mutations map to a previously proposed pyrethroid-receptor site in the house fly sodium channel, the other three mutations are mapped to a second receptor site. Discovery of this second putative receptor site provides a dual-receptor paradigm that could explain much of the molecular mechanisms of pyrethroid action and resistance as well as the high selectivity of pyrethroids on insect vs. mammalian sodium channels. Results from this study could impact future prediction and monitoring of pyrethroid resistance in mosquitoes and other arthropod pests and disease vectors.

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confidence: 65%

Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel

Nomura

Satar

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

267

398

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“…The role of domain II in promoting activation is demonstrated by the effect of ␤-scorpion toxin and insecticides, which have been shown to bind to S1-S2 and S3-S4 or S4 -S5 and S5 sections of domain II in Drosophila sodium channels and Na v 1.4, stabilizing the voltage sensor in its activated state (55,56). The voltage dependence of the toxin-modified channel is shifted to more negative potentials.…”

Section: Discussionmentioning

confidence: 99%

A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation

Lampert

O’Reilly

Dib‐Hajj

et al. 2008

Journal of Biological Chemistry

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Sodium channel Na v 1.7 has recently elicited considerable interest as a key contributor to human pain. Gain-of-function mutations of Na v 1.7 produce painful disorders, whereas loss-offunction Na v 1.7 mutations produce insensitivity to pain. The inherited erythromelalgia Na v 1.7/F1449V mutation, within the C terminus of domain III/transmembrane helix S6, shifts channel activation by ؊7.2 mV and accelerates time to peak, leading to nociceptor hyperexcitability. We constructed a homology model of Na v 1.7, based on the KcsA potassium channel crystal structure, which identifies four phylogenetically conserved aromatic residues that correspond to DIII/F1449 at the C-terminal end of each of the four S6 helices. The model predicted that changes in side-chain size of residue 1449 alter the pore's cytoplasmic aperture diameter and reshape inter-domain contact surfaces that contribute to closed state stabilization. To test this hypothesis, we compared activation of wild-type and mutant Na v 1.7 channels F1449V/L/Y/W by whole cell patch clamp analysis. All but the F1449V mutation conserve the voltage dependence of activation. Compared with wild type, time to peak was shorter in F1449V, similar in F1449L, but longer for F1449Y and F1449W, suggesting that a bulky, hydrophobic residue is necessary for normal activation. We also substituted the corresponding aromatic residue of S6 in each domain individually with valine, to mimic the naturally occurring Na v 1.7 mutation. We show that DII/F960V and DIII/F1449V, but not DI/Y405V or DIV/F1752V, regulate Na v 1.7 activation, consistent with well established conformational changes in DII and DIII. We propose that the four aromatic residues contribute to the gate at the cytoplasmic pore aperture, and that their ring side chains form a hydrophobic plug which stabilizes the closed state of Na v 1.7.

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“…Although no superkdr mutation has so far been identified in mosquitoes, it was suggested that Leu932Phe, in association with Ile936Val (both also in the IIS4-S5 linker), in Culex might play this role, being the first example of super-kdr in this group (T. G. Davies et al, 2007a). Accordingly, these sites have proved to be important for the interaction between Na V , in the D. melanogaster sodium channel and pyrethroids or DDT (Usherwood et al, 2007). Substitutions in site 929 are also involved in enhanced pyrethroid resistance, as is the case with the Lepidoptera Plutella xylostella mutation Thr929Ile, detected in association with Leu1014Phe (Schuler et al, 1998).…”

Section: The Kdr Mutationmentioning

confidence: 99%

The Pyrethroid Knockdown Resistance

Martins¹,

Valle²

2012

Insecticides - Basic and Other Applications

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Mutations in DIIS5 and the DIIS4–S5 linker ofDrosophila melanogastersodium channel define binding domains for pyrethroids and DDT

Cited by 117 publications

References 20 publications

Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel

Molecular evidence for dual pyrethroid-receptor sites on a mosquito sodium channel

A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation

The Pyrethroid Knockdown Resistance

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