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David M Soderlund - One of the best experts on this subject based on the ideXlab platform.
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evidence for a separate mechanism of toxicity for the type i and the type ii pyrethroid insecticides
Neurotoxicology, 2009Co-Authors: Charles B Breckenridge, David M Soderlund, Nicholas C Sturgess, Dana Sargent, Jinsung Choi, Steve Symington, Larry R Holden, Myra L Weiner, Larry P Sheets, Marshall J ClarkAbstract:Abstract Neurotoxicity and mechanistic data were collected for six α-cyano pyrethroids (β-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and λ-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, Cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na v 1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T-syndrome—tremors) and Type II (CS syndrome—choreoathetosis with salivation) groups based on FOB data. Of the α-cyano pyrethroids, deltamethrin, λ-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six α-cyano pyrethroids (λ-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of λ-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, Cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, λ-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups.
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Evidence for a separate mechanism of toxicity for the Type I and the Type II pyrethroid insecticides.
Neurotoxicology, 2009Co-Authors: Charles B Breckenridge, David M Soderlund, Nicholas C Sturgess, Dana Sargent, Jinsung Choi, Steve Symington, Larry Holden, Myra Weiner, Larry Sheets, J. Marshall ClarkAbstract:Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, Cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. Of the alpha-cyano pyrethroids, deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six alpha-cyano pyrethroids (lambda-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of lambda-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, Cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups.
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Structure–activity relationships for the action of 11 pyrethroid insecticides on rat Nav1.8 sodium channels expressed in Xenopus oocytes
Toxicology and Applied Pharmacology, 2005Co-Authors: Jinsung Choi, David M SoderlundAbstract:Pyrethroid insecticides bind to voltage-sensitive sodium channels and modify their gating kinetics, thereby disrupting nerve function. This paper describes the action of 11 structurally diverse commercial pyrethroid insecticides on the rat Na v 1.8 sodium channel isoform, the principal carrier of the tetrodotoxin-resistant, pyrethroid-sensitive sodium current of sensory neurons, expressed in Xenopus laevis oocytes. All 11 compounds produced characteristic sodium tail currents following a depolarizing pulse that ranged from rapidly-decaying monoexponential currents (allethrin, Cismethrin and permethrin) to persistent biexponential currents (cyfluthrin, cyhalothrin, cypermethrin and deltamethrin). Tail currents for the remaining compounds (bifenthrin, fenpropathrin, fenvalerate and tefluthrin) were monoexponential and decayed with kinetics intermediate between these extremes. Reconstruction of currents carried solely by the pyrethroid-modified subpopulation of channels revealed two types of pyrethroid-modified currents. The first type, found with Cismethrin, allethrin, permethrin and tefluthrin, activated relatively rapidly and inactivated partially during a 40-ms depolarization. The second type, found with cypermethrin, cyfluthrin, cyhalothrin, deltamethrin, fenpropathrin and fenvalerate, activated more slowly and did not detectably inactivate during a 40-ms depolarization. Only bifenthrin did not produce modified currents that fit clearly into either of these categories. In all cases, the rate of activation of modified channels was strongly correlated with the rate of tail current decay following repolarization. Modification of Na v 1.8 sodium channels by cyfluthrin, cyhalothrin, cypermethrin and deltamethrin was enhanced 2.3- to 3.4-fold by repetitive stimulation; this effect appeared to result from the accumulation of persistently open channels rather than preferential binding to open channel states. Fenpropathrin was the most effective compound against Na v 1.8 sodium channels from the perspective of either resting or use-dependent modification. When use dependence is taken into account, cypermethrin, deltamethrin and tefluthrin approached the effectiveness of fenpropathrin. The selective expression of Na v 1.8 sodium channels in nociceptive neurons suggests that these channels may be important targets for pyrethroids in the production of paresthesia following dermal exposure.
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Point Mutations in Homology Domain II Modify the Sensitivity of Rat Nav1.8 Sodium Channels to the Pyrethroid Insecticide Cismethrin
Neurotoxicology, 2001Co-Authors: David M Soderlund, Si Hyeock LeeAbstract:Abstract Two point mutations in homology domain II of the house fly Vssc1 voltage-sensitive sodium channel α subunit, M918T and L1014F, are associated with resistance to pyrethroid insecticides and reduce the pyrethroid sensitivity of Vssc1 sodium channels expressed in Xenopus laevis oocytes. To assess the impact of these residues as determinants of pyrethroid sensitivity in another sequence context, we mutated the corresponding positions of the rat pyrethroid-sensitive, TTX-resistant peripheral nerve sodium channel (rNav1.8; also called SNS or PN3) and determined the sensitivity of native and mutated channels expressed in Xenopus oocytes to the pyrethroid insecticide Cismethrin. The rNav1.8 channel, like other vertebrate sodium channel isoforms, contains a conserved isoleucine residue at sequence position 780 that aligns with the conserved methionine at position 918 of Vssc1 and other insect sodium channels. Channels mutated to contain methionine at position 780 (I780M) exhibited enhanced sensitivity to Cismethrin and larger decay constants for pyrethroid-modified channel states. In contrast, the mutation corresponding to M918T in the Vssc1 channel (I780T) profoundly decreased the Cismethrin sensitivity of expressed channels. Insertion of the mutation corresponding to L1014F (L879F in rNav1.8) reduced the Cismethrin sensitivity of channels having either isoleucine or methionine at position 780, whereas channels containing the I780T/L879F double mutation were insensitive to this insecticide. Mutations at Ile780 and Leu879 also modified the voltage dependence of rNav1.8 channels, but these effects were not related to changes in pyrethroid sensitivity. These results confirm the importance of residues in homology domain II as fundamental determinants of the pyrethroid sensitivity of sodium channels.
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Potent Actions of the Pyrethroid Insecticides Cismethrin and Cypermethrin on Rat Tetrodotoxin-Resistant Peripheral Nerve (SNS/PN3) Sodium Channels Expressed in Xenopus Oocytes
Pesticide Biochemistry and Physiology, 2001Co-Authors: Timothy J. Smith, David M SoderlundAbstract:Abstract The rat peripheral nerve tetrodotoxin (TTX)-resistant voltage-sensitive sodium channel (designated SNS/PN3) was expressed in Xenopus laevis oocytes, and the responses of the expressed channels to two pyrethroid insecticides, Cismethrin and cypermethrin, were assessed by recording macroscopic sodium currents under voltage clamp conditions. Each pyrethroid produced two distinct modifications of sodium currents carried by SNS/PN3 channels: a sustained, slowly inactivating current evident during a depolarizing pulse and a prominent tail current following repolarization. In addition, high concentrations of Cismethrin produced a reduction of the amplitude of the peak transient sodium current. Cismethrin-induced tail currents decayed with a first-order decay constant (τ) of 14.7 ms, whereas cypermethrin-induced tail currents were much more persistent (τ = 558 ms). Modified currents were obtained in the presence of nanomolar concentrations of each compound, and the amplitude of the modified currents exhibited a strong concentration dependence. High concentrations of Cismethrin and cypermethrin shifted the voltage dependence of activation of SNS/PN3 sodium channels by ∼5 mV in the direction of hyperpolarization and the voltage dependence of steady-state inactivation by ∼8–10 mV in the direction of depolarization. The high sensitivity of the SNS/PN3 sodium channel to pyrethroids is consistent with the identification of this channel isoform as the principal carrier of the TTX-resistant, pyrethroid-sensitive sodium current of dorsal root ganglion neurons.
Timothy J. Smith - One of the best experts on this subject based on the ideXlab platform.
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Potent Actions of the Pyrethroid Insecticides Cismethrin and Cypermethrin on Rat Tetrodotoxin-Resistant Peripheral Nerve (SNS/PN3) Sodium Channels Expressed in Xenopus Oocytes
Pesticide Biochemistry and Physiology, 2001Co-Authors: Timothy J. Smith, David M SoderlundAbstract:Abstract The rat peripheral nerve tetrodotoxin (TTX)-resistant voltage-sensitive sodium channel (designated SNS/PN3) was expressed in Xenopus laevis oocytes, and the responses of the expressed channels to two pyrethroid insecticides, Cismethrin and cypermethrin, were assessed by recording macroscopic sodium currents under voltage clamp conditions. Each pyrethroid produced two distinct modifications of sodium currents carried by SNS/PN3 channels: a sustained, slowly inactivating current evident during a depolarizing pulse and a prominent tail current following repolarization. In addition, high concentrations of Cismethrin produced a reduction of the amplitude of the peak transient sodium current. Cismethrin-induced tail currents decayed with a first-order decay constant (τ) of 14.7 ms, whereas cypermethrin-induced tail currents were much more persistent (τ = 558 ms). Modified currents were obtained in the presence of nanomolar concentrations of each compound, and the amplitude of the modified currents exhibited a strong concentration dependence. High concentrations of Cismethrin and cypermethrin shifted the voltage dependence of activation of SNS/PN3 sodium channels by ∼5 mV in the direction of hyperpolarization and the voltage dependence of steady-state inactivation by ∼8–10 mV in the direction of depolarization. The high sensitivity of the SNS/PN3 sodium channel to pyrethroids is consistent with the identification of this channel isoform as the principal carrier of the TTX-resistant, pyrethroid-sensitive sodium current of dorsal root ganglion neurons.
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potent actions of the pyrethroid insecticides Cismethrin and cypermethrin on rat tetrodotoxin resistant peripheral nerve sns pn3 sodium channels expressed in xenopus oocytes
Pesticide Biochemistry and Physiology, 2001Co-Authors: Timothy J. Smith, David M SoderlundAbstract:Abstract The rat peripheral nerve tetrodotoxin (TTX)-resistant voltage-sensitive sodium channel (designated SNS/PN3) was expressed in Xenopus laevis oocytes, and the responses of the expressed channels to two pyrethroid insecticides, Cismethrin and cypermethrin, were assessed by recording macroscopic sodium currents under voltage clamp conditions. Each pyrethroid produced two distinct modifications of sodium currents carried by SNS/PN3 channels: a sustained, slowly inactivating current evident during a depolarizing pulse and a prominent tail current following repolarization. In addition, high concentrations of Cismethrin produced a reduction of the amplitude of the peak transient sodium current. Cismethrin-induced tail currents decayed with a first-order decay constant (τ) of 14.7 ms, whereas cypermethrin-induced tail currents were much more persistent (τ = 558 ms). Modified currents were obtained in the presence of nanomolar concentrations of each compound, and the amplitude of the modified currents exhibited a strong concentration dependence. High concentrations of Cismethrin and cypermethrin shifted the voltage dependence of activation of SNS/PN3 sodium channels by ∼5 mV in the direction of hyperpolarization and the voltage dependence of steady-state inactivation by ∼8–10 mV in the direction of depolarization. The high sensitivity of the SNS/PN3 sodium channel to pyrethroids is consistent with the identification of this channel isoform as the principal carrier of the TTX-resistant, pyrethroid-sensitive sodium current of dorsal root ganglion neurons.
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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
Insect Biochemistry and Molecular Biology, 1999Co-Authors: Timothy J. Smith, Douglas C Knipple, David M SoderlundAbstract:Abstract The super-kdr insecticide resistance trait of the house fly confers resistance to pyrethroids and DDT by reducing the sensitivity of the fly nervous system. The super-kdr genetic locus is tightly linked to the Vssc1 gene, which encodes a voltage-sensitive sodium channel α subunit that is the principal site of pyrethroid action. DNA sequence analyses of Vssc1 alleles from several independent super-kdr fly strains identified two amino acid substitutions associated with the super-kdr trait: replacement of leucine at position 1014 with phenylalanine (L1014F), which has been shown to cause the kdr resistance trait in this species, and replacement of methionine at position 918 with threonine (M918T). We examined the functional significance of these mutations by expressing house fly sodium channels containing them in Xenopus laevis oocytes and by characterizing the biophysical properties and pyrethroid sensitivities of the expressed channels using two-electrode voltage clamp. House fly sodium channels that were specifically modified by site-directed mutagenesis to contain the M918T/L1014F double mutation gave reduced levels of sodium current expression in oocytes but otherwise exhibited functional properties similar to those of wildtype channels and channels containing the L1014F substitution. However, M918T/L1014F channels were completely insensitive to high concentrations of the pyrethroids Cismethrin and cypermethrin. House fly sodium channels specifically modified to contain the M918T single mutation, which is not known to exist in nature except in association with the L1014F mutation, gave very small sodium currents in oocytes. Assays of these currents in the presence of high concentrations of Cismethrin suggest that this mutation alone is sufficient to abolish the pyrethroid sensitivity of house fly sodium channels. These results define the functional significance of the Vssc1 mutations associated with the super-kdr trait of the house fly and are consistent with the hypothesis that the super-kdr trait arose by selection of a second-site mutation (M918T) that confers to flies possessing it even greater resistance than the kdr allele containing the L1014F mutation.
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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.
Insect Biochemistry and Molecular Biology, 1999Co-Authors: Si Hyeock Lee, Douglas C Knipple, Timothy J. Smith, David M SoderlundAbstract:The super-kdr insecticide resistance trait of the house fly confers resistance to pyrethroids and DDT by reducing the sensitivity of the fly nervous system. The super-kdr genetic locus is tightly linked to the Vssc1 gene, which encodes a voltage-sensitive sodium channel alpha subunit that is the principal site of pyrethroid action. DNA sequence analysis of Vssc1 alleles from several independent super-kdr fly strains identified two amino acid substitutions associated with the super-kdr trait: replacement of leucine at position 1014 with phenylalanine (L1014F), which has been shown to cause the kdr resistance trait in this species, and replacement of methionine at position 918 with threonine (M918T). We examined the functional significance of these mutations by expressing house fly sodium channels containing them in Xenopus laevis oocytes and by characterizing the biophysical properties and pyrethroid sensitivities of the expressed channels using two-electrode voltage clamp. House fly sodium channels that were specifically modified by site-directed mutagenesis to contain the M918T/L1014F double mutation gave reduced levels of sodium current expression in oocytes but otherwise exhibited functional properties similar to those of wildtype channels and channels containing the L1014F substitution. However, M918T/L1014F channels were completely insensitive to high concentrations of the pyrethroids Cismethrin and cypermethrin. House fly sodium channels specifically modified to contain the M918T single mutation, which is not known to exist in nature except in association with the L1014F mutation, gave very small sodium currents in oocytes. Assays of these currents in the presence of high concentrations of Cismethrin suggest that this mutation alone is sufficient to abolish the pyrethroid sensitivity of house fly sodium channels. These results define the functional significance of the Vssc1 mutations associated with the super-kdr trait of the house fly and are consistent with the hypothesis that the super-kdr trait arose by selection of a second-site mutation (M918T) that confers to flies possessing it even greater resistance than the kdr allele containing the L1014F mutation.
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Actions of the pyrethroid insecticides Cismethrin and cypermethrin on house fly Vssc1 sodium channels expressed in Xenopus oocytes
Archives of Insect Biochemistry and Physiology, 1998Co-Authors: Timothy J. Smith, Patricia J Ingles, David M SoderlundAbstract:Voltage-sensitive sodium channels encoded by the Vssc1 gene of the house fly (Musca domestica) were expressed in Xenopus laevis oocytes in combination with the tipE gene product of Drosophila melanogaster and were characterized by two-electrode voltage clamp. Vssc1/tipE sodium channels expressed in oocytes were highly sensitive to tetrodotoxin; half-maximal inhibition of sodium currents by tetrodotoxin was obtained at a concentration of 2.4 nM. Cismethrin, a pyrethroid that produces Type I effects on intact nerve, slowed the inactivation of sodium currents carried by Vssc1/tipE channels during a depolarizing pulse and induced a tail current after repolarization that decayed with a first-order time constant of approximately 650 ms. The voltage dependence of activation and steady-state inactivation of Cismethrin-modified channels were shifted to more negative potentials. Cypermethrin, a pyrethroid with Type II effects on intact nerve, also prolonged the inactivation of Vssc1/tipE sodium channels and induced a tail current. However, the cypermethrin-induced tail current was extremely persistent, decaying with a first-order time constant of approximately 42 s. Unlike Cismethrin, the effect of cypermethrin was use dependent, requiring repeated depolarizing pulses for the full development of modified sodium currents. The divergent effects of Cismethrin and cypermethrin on Vssc1/tipE sodium channels expressed in oocytes are consistent with the actions of these and related compounds on sodium channels in invertebrate and vertebrate nerve preparations and provide insight into the mechanisms underlying the production of Type I and II effects on neuronal excitability. Arch. Insect Biochem. Physiol. 38:126–136, 1998. © 1998 Wiley-Liss, Inc.
Douglas C Knipple - One of the best experts on this subject based on the ideXlab platform.
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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.
Insect Biochemistry and Molecular Biology, 1999Co-Authors: Si Hyeock Lee, Douglas C Knipple, Timothy J. Smith, David M SoderlundAbstract:The super-kdr insecticide resistance trait of the house fly confers resistance to pyrethroids and DDT by reducing the sensitivity of the fly nervous system. The super-kdr genetic locus is tightly linked to the Vssc1 gene, which encodes a voltage-sensitive sodium channel alpha subunit that is the principal site of pyrethroid action. DNA sequence analysis of Vssc1 alleles from several independent super-kdr fly strains identified two amino acid substitutions associated with the super-kdr trait: replacement of leucine at position 1014 with phenylalanine (L1014F), which has been shown to cause the kdr resistance trait in this species, and replacement of methionine at position 918 with threonine (M918T). We examined the functional significance of these mutations by expressing house fly sodium channels containing them in Xenopus laevis oocytes and by characterizing the biophysical properties and pyrethroid sensitivities of the expressed channels using two-electrode voltage clamp. House fly sodium channels that were specifically modified by site-directed mutagenesis to contain the M918T/L1014F double mutation gave reduced levels of sodium current expression in oocytes but otherwise exhibited functional properties similar to those of wildtype channels and channels containing the L1014F substitution. However, M918T/L1014F channels were completely insensitive to high concentrations of the pyrethroids Cismethrin and cypermethrin. House fly sodium channels specifically modified to contain the M918T single mutation, which is not known to exist in nature except in association with the L1014F mutation, gave very small sodium currents in oocytes. Assays of these currents in the presence of high concentrations of Cismethrin suggest that this mutation alone is sufficient to abolish the pyrethroid sensitivity of house fly sodium channels. These results define the functional significance of the Vssc1 mutations associated with the super-kdr trait of the house fly and are consistent with the hypothesis that the super-kdr trait arose by selection of a second-site mutation (M918T) that confers to flies possessing it even greater resistance than the kdr allele containing the L1014F mutation.
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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
Insect Biochemistry and Molecular Biology, 1999Co-Authors: Timothy J. Smith, Douglas C Knipple, David M SoderlundAbstract:Abstract The super-kdr insecticide resistance trait of the house fly confers resistance to pyrethroids and DDT by reducing the sensitivity of the fly nervous system. The super-kdr genetic locus is tightly linked to the Vssc1 gene, which encodes a voltage-sensitive sodium channel α subunit that is the principal site of pyrethroid action. DNA sequence analyses of Vssc1 alleles from several independent super-kdr fly strains identified two amino acid substitutions associated with the super-kdr trait: replacement of leucine at position 1014 with phenylalanine (L1014F), which has been shown to cause the kdr resistance trait in this species, and replacement of methionine at position 918 with threonine (M918T). We examined the functional significance of these mutations by expressing house fly sodium channels containing them in Xenopus laevis oocytes and by characterizing the biophysical properties and pyrethroid sensitivities of the expressed channels using two-electrode voltage clamp. House fly sodium channels that were specifically modified by site-directed mutagenesis to contain the M918T/L1014F double mutation gave reduced levels of sodium current expression in oocytes but otherwise exhibited functional properties similar to those of wildtype channels and channels containing the L1014F substitution. However, M918T/L1014F channels were completely insensitive to high concentrations of the pyrethroids Cismethrin and cypermethrin. House fly sodium channels specifically modified to contain the M918T single mutation, which is not known to exist in nature except in association with the L1014F mutation, gave very small sodium currents in oocytes. Assays of these currents in the presence of high concentrations of Cismethrin suggest that this mutation alone is sufficient to abolish the pyrethroid sensitivity of house fly sodium channels. These results define the functional significance of the Vssc1 mutations associated with the super-kdr trait of the house fly and are consistent with the hypothesis that the super-kdr trait arose by selection of a second-site mutation (M918T) that confers to flies possessing it even greater resistance than the kdr allele containing the L1014F mutation.
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the l1014f point mutation in the house fly vssc1 sodium channel confers knockdown resistance to pyrethroids
Insect Biochemistry and Molecular Biology, 1997Co-Authors: Timothy J. Smith, Patricia J Ingles, Douglas C Knipple, David M SoderlundAbstract:Voltage-sensitive sodium channels encoded by a full-length cDNA corresponding to the Vssc1 gene of the house fly (Musca domestica) were expressed in Xenopus laevis oocytes either alone or in combination with the tipE gene product of Drosophila melanogaster and were characterized by two-electrode voltage clamp. Vssc1 cRNA alone produced very small (50–150 nA) sodium currents, whereas the combination of Vssc1 and tipE cRNAs produced robust (0.5–3 μA), rapidly inactivating sodium currents. The pyrethroid insecticide Cismethrin prolonged the sodium current carried by Vssc1/tipE sodium channels during a depolarizing pulse and induced a tail current after repolarization. The Vssc1 cDNA was specifically mutated to substitute phenylalanine for leucine at position 1014 of the inferred amino acid sequence (L1014F), a polymorphism shown previously to be associated with the kdr (knockdown resistance) trait of the house fly. The L1014F substitution reduced the sensitivity of expressed house fly sodium channels to Cismethrin at least 10-fold and increased the rate of decay of pyrethroid-induced sodium tail currents. These results demonstrate that the resistance-associated L1014F mutation confers a reduction in the sensitivity of house fly sodium channels to pyrethroids that is sufficient to account for the kdr resistance trait.
David E. Ray - One of the best experts on this subject based on the ideXlab platform.
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Structure-activity and interaction effects of 14 different pyrethroids on voltage-gated chloride ion channels
2016Co-Authors: Steven A Burr, David E. RayAbstract:ow nloaded from We have proposed that since the type II pyrethroids deltamethrin and cypermethrin, but not the type I pyrethroid Cismethrin act on chloride channels, this could contribute to the bimodal nature of pyrethroid poisoning syndromes. We now examine a wider range of pyrethroid structures on the activity of these calcium-independent voltage-gated maxi-chloride channels. Excised inside-out membrane patches from differentiated mouse neuroblastoma cells were used, and mean channel open probabilities calculated. For single dosing at 10 µM, bioallethrin, -cyfluthrin, cypermethrin, deltamethrin and fenpropathrin were all found to significantly decrease open channel probability (p<0.05). Bifenthrin, bioresmethrin, cispermethrin, cisresmethrin, cyfluthrin isomers 2 and 4, -cyhalothrin, esfenvalerate and tefluthrin, did not significantly alter open channel probability (p>0.05). Since the type II pyrethroids, esfenvalerate and -cyhalothrin were ineffective, we must conclude that actions at the chloride ion channel target cannot in themselves account for the differences between the two types of poisoning syndrome. Sequential dosing with type II pyrethroids caused no further chloride ion channel closure. The type I pyrethroid cisresmethrin did however prevent a subsequent effect by the mixed type pyrethroid fenpropathrin. In contrast, the type I pyrethroid cispermethrin did not prevent a subsequent effect due to the type II pyrethroid deltamethrin. The difference in effect may be the result of differences in potency, as deltamethrin had a greater effect than fenpropathrin. It therefore appears clear that in some combinations the type I and type II pyrethroids can compete and may bind to the same chloride channel target site
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structure activity and interaction effects of 14 different pyrethroids on voltage gated chloride ion channels
Toxicological Sciences, 2004Co-Authors: Steven A Burr, David E. RayAbstract:We have proposed that since the type II pyrethroids deltamethrin and cypermethrin, but not the type I pyrethroid Cismethrin act on chloride channels, this could contribute to the bimodal nature of pyrethroid poisoning syndromes. We now examine a wider range of pyrethroid structures on the activity of these calcium-independent voltage-gated maxi-chloride channels. Excised inside-out membrane patches from differentiated mouse neuroblastoma cells were used, and mean channel open probabilities calculated. For single dosing at 10 M, bioallethrin, -cyfluthrin, cypermethrin, deltamethrin, and fenpropathrin were all found to significantly decrease open channel probability (p 0.05). Since the type II pyrethroids, esfenvalerate, and -cyhalothrin were ineffective, we must conclude that actions at the chloride ion channel target cannot in themselves account for the differences between the two types of poisoning syndrome. Sequential dosing with type II pyrethroids caused no further chloride ion channel closure. The type I pyrethroid cisresmethrin did however prevent a subsequent effect by the mixed type pyrethroid fenpropathrin. In contrast, the type I pyrethroid cispermethrin did not prevent a subsequent effect due to the type II pyrethroid deltamethrin. The difference in effect may be the result of differences in potency, as deltamethrin had a greater effect than fenpropathrin. It therefore appears clear that in some combinations the type I and type II pyrethroids can compete and may bind to the same chloride channel target site.
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Structure-Activity and Interaction Effects of 14 Different Pyrethroids on Voltage-Gated Chloride Ion Channels
2003Co-Authors: Steven A Burr, David E. RayAbstract:We have proposed that since the type II pyrethroids deltamethrin and cypermethrin, but not the type I pyrethroid Cismethrin act on chloride channels, this could contribute to the bimodal nature of pyrethroid poisoning syndromes. We now examine a wider range of pyrethroid structures on the activity of these calcium-independent voltage-gated maxi-chloride channels. Excised inside-out membrane patches from differentiated mouse neuroblastoma cells were used, and mean channel open probabilities calculated. For single dosing at 10 �M, bioallethrin, �-cyfluthrin, cypermethrin, deltamethrin, and fenpropathrin were all found to significantly decrease open channel probability (p < 0.05). Bifenthrin, bioresmethrin, cispermethrin, cisresmethrin, cyfluthrin isomers 2 and 4, �-cyhalothrin, esfenvalerate, and tefluthrin, did not significantly alter open channel probability (p> 0.05). Since the type II pyrethroids, esfenvalerate, and �-cyhalothri
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Actions of pyrethroid insecticides on voltage-gated chloride channels in neuroblastoma cells.
Neurotoxicology, 1997Co-Authors: David E. Ray, Sutharsan SAbstract:Pyrethroid insecticides have the potential to act at several sites in excitable tissues in addition to their primary effect on sodium channels. We have assessed one such site, the voltage gated chloride channel. Following our previous demonstration of actions of deltamethrin on the voltage-gated chloride channel in rats and in neuroblastoma cells, we examined the dose-response relationship for deltamethrin by patch clamp analysis of voltage-gated channels in partially differentiated NIE115 cells. Open channel probability (P0) was assessed in channels stepped from 0 to +20 mV for 10 seconds. Deltamethrin significantly decreased P0 by 0.237+/-0.070 at 10(-10) M and, although construction of a dose-response relationship was rendered difficult by the very low water solubility of the pyrethroids, a decrease of 0.968+/-0.140 was reached at the highest concentration tested, 10(-4) M. A second Type II pyrethroid cypermethrin also decreased P0, by 0.430+/-0.09 at 5 x 10(-6) M, but the Type I pyrethroid Cismethrin produced a decrease of only 0.188+/-0.08 at 2 x 10(-5) M. These effects were seen in 340 pS conductance, calcium-independent channels. A sample of 9 calcium-dependent channels with a conductance of 225 pS failed to show any response to deltamethrin. We conclude that actions on calcium-independent voltage-gated chloride channels are likely to contribute significantly to type II pyrethroid toxicity.
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Characteristics of the prolonged inhibition produced by a range of pyrethroids in the rat hippocampus.
Toxicology and Applied Pharmacology, 1990Co-Authors: Robert M. Joy, David E. Ray, T. Lister, M.p. SevilleAbstract:Abstract Eight different synthetic pyrethroids were examined to determine their effects on the excitability of hippocampal granule cells in urethane-anesthetized rats. A paired stimulus approach was used. All eight prolonged the depression of granule cell excitability that follows stimulation of their major synaptic input, the perforant path. The magnitude of this effect depended upon the class to which the pyrethroid belonged. Type I pyrethroids (those primarily producing tremor) prolonged the depression of granule cell excitability for shorter periods than did type II pyrethroids (those primarily producing salivation and choreoathetosis) or pyrethroids producing a mixed type of intoxication. No overlap was found between groups. To determine whether the difference observed between type I and type II pyrethroids was the result of an infelicitous selection of doses, Cismethrin (type I) was tested over a dose range of 1.5–24 times the conscious rat iv LD50. Even at the highest dose, the prolongation remained well below that produced by type II pyrethroids. The effect of deltamethrin was shown to be consistent with the production or potentiation of a surmountable inhibitory response. This action of deltamethrin was antagonizable by mephenesin and lidocaine, but not by picrotoxin or halothane. The type of effect, its time course, and the antagonism data suggest that type II pyrethroids enhance inhibition in the dentate gyrus. This action does not appear to be mediated by GABA A receptors.
T. Lister - One of the best experts on this subject based on the ideXlab platform.
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the role of voltage gated chloride channels in type ii pyrethroid insecticide poisoning
Toxicology and Applied Pharmacology, 2000Co-Authors: Philip J. Forshaw, T. ListerAbstract:Abstract Pyrethroids act on mammalian sodium channels, but we have previously shown that low concentrations of the type II pyrethroid deltamethrin also decrease the open channel probability ( P o ) of voltage-gated chloride channels. This effect would be expected to amplify the sodium channel-mediated signs of poisoning produced by pyrethroids. In the present study we evaluated potential chloride channel agonists in vitro, and then tested the most effective of these on pyrethroid-poisoned rats to determine the practical significance of chloride channel effects in vivo. Patch clamp experiments showed that, for voltage-gated maxi chloride channels in excised, inside-out patches from mouse N1E 115 neuroblastoma cells, ivermectin (10 −7 M) and pentobarbitone (10 −6 M) significantly increased open channel probability ( p ≤ 0.01 and p ≤ 0.02, respectively), whereas phenobarbitone, hexobarbitone, mephobarbitone, thiopentone, and barbituric acid did not. This suggested that, if chloride channels were important in vivo, ivermectin and pentobarbitone should antagonize type II pyrethroid poisoning and phenobarbitone should not. Male F344 rats were then pretreated with ivermectin (4 mg/kg iv), equisedative doses of either pentobarbitone (15 mg/kg ip) or phenobarbitone (45 mg/kg ip), or solvent controls. This was followed by deltamethrin (1.5 or 2 mg/kg iv) or the type I pyrethroid Cismethrin (4 mg/kg iv). Ivermectin produced a marked fall in deltamethrin-induced salivation ( p ≤ 0.05) and also (in anesthetized rats) in repetitive electromyogram discharge and muscle twitch ( p ≤ 0.01 and p ≤ 0.05, respectively). Pentobarbitone significantly reduced the motor signs score due to deltamethrin ( p ≤ 0.01). Ivermectin therefore protected against the peripheral signs of deltamethrin poisoning and pentobarbitone protected against the central signs. As expected phenobarbitone had no protective effects. The motor signs produced by the type I pyrethroid Cismethrin (which does not act on chloride channels) were not diminished by either barbiturate. The peripheral benzodiazepine receptor blocker PK11195 did not diminish the protective action of ivermectin on the muscle twitch ( p ≤ 0.05), although it partially reversed the block of salivation ( p ≤ 0.05). These results support the hypothesis that the voltage-dependent chloride channel is a toxicologically significant additional site of action for deltamethrin and that the use of chloride channel agonists can provide a rationale for a novel and effective therapy against type II pyrethroid poisoning.
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Characteristics of the prolonged inhibition produced by a range of pyrethroids in the rat hippocampus.
Toxicology and Applied Pharmacology, 1990Co-Authors: Robert M. Joy, David E. Ray, T. Lister, M.p. SevilleAbstract:Abstract Eight different synthetic pyrethroids were examined to determine their effects on the excitability of hippocampal granule cells in urethane-anesthetized rats. A paired stimulus approach was used. All eight prolonged the depression of granule cell excitability that follows stimulation of their major synaptic input, the perforant path. The magnitude of this effect depended upon the class to which the pyrethroid belonged. Type I pyrethroids (those primarily producing tremor) prolonged the depression of granule cell excitability for shorter periods than did type II pyrethroids (those primarily producing salivation and choreoathetosis) or pyrethroids producing a mixed type of intoxication. No overlap was found between groups. To determine whether the difference observed between type I and type II pyrethroids was the result of an infelicitous selection of doses, Cismethrin (type I) was tested over a dose range of 1.5–24 times the conscious rat iv LD50. Even at the highest dose, the prolongation remained well below that produced by type II pyrethroids. The effect of deltamethrin was shown to be consistent with the production or potentiation of a surmountable inhibitory response. This action of deltamethrin was antagonizable by mephenesin and lidocaine, but not by picrotoxin or halothane. The type of effect, its time course, and the antagonism data suggest that type II pyrethroids enhance inhibition in the dentate gyrus. This action does not appear to be mediated by GABA A receptors.