The Experts below are selected from a list of 5958 Experts worldwide ranked by ideXlab platform
Toshio Narahashi - One of the best experts on this subject based on the ideXlab platform.
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Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310(1
2020Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:ABSTRACT Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC 50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin
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glutamate activated chloride channels unique Fipronil targets present in insects but not in mammals
Pesticide Biochemistry and Physiology, 2010Co-Authors: Toshio Narahashi, Xilong Zhao, Vincent L Salgado, Tomoko Ikeda, Jay Z YehAbstract:Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of Fipronil. The IC(50)s of Fipronil block were 30 nM in cockroach GABA receptors and 1600 nM in rat GABA(A) receptors. Moreover, GluCls of cockroach neurons had low IC(50)s for Fipronil. Two types of glutamate-induced chloride current were obswerved: desensitizing and non-desensitizing, with Fipronil IC(50)s of 800 and 10 nM, respectively. We have developed methods to separately record these two types of GluCls. The non-desensitizing and desensitizing currents were selectively inhibited by trypsin and polyvinylpyrrolidone, respectively. In conclusion, in addition to GABA receptors, GluCls play a crucial role in selectivity of Fipronil to insects over mammals. GluCls form the basis for development of selective and safe insecticides.
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Fipronil is a potent open channel blocker of glutamate activated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.
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differential actions of Fipronil and dieldrin insecticides on gaba gated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to Fipronil and dieldrin. We examined differential actions of Fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas Fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of Fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.
Sarfraz Ali Shad - One of the best experts on this subject based on the ideXlab platform.
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cross resistance genetics and realized heritability of resistance to Fipronil in the house fly musca domestica diptera muscidae a potential vector for disease transmission
Parasitology Research, 2014Co-Authors: Naeem Abbas, Hafiz Azhar Ali Khan, Sarfraz Ali ShadAbstract:Houseflies, Musca domestica (L.), are ubiquitous pests that have the potential to spread a variety of pathogens to humans, poultries, and dairies. Pesticides are commonly used for the management of this pest. Fipronil is a GABA-gated chloride channel-inhibiting insecticide that has been commonly used for the management of different pests including M. domestica throughout the world. Many pests have developed resistance to this insecticide. A field-collected strain of M. domestica was selected with Fipronil for continuous 11 generations to assess the cross-resistance, genetics, and realized heritability for designing a resistance management strategy. Laboratory bioassays were performed using the feeding method of mixing insecticide concentrations with 20 % sugar solutions and cotton soaks dipped in insecticide solutions were provided to tested adult flies. Bioassay results at G12 showed that the Fipronil-selected strain developed a resistance ratio of 140-fold compared to the susceptible strain. Synergism bioassay with piperonyl butoxide (PBO) and S,S,S,-tributyl phosphorotrithioate (DEF) indicated that Fipronil resistance was associated with microsomal oxidase and also esterase. Reciprocal crosses between resistant and susceptible strains showed an autosomal and incompletely dominant resistance to Fipronil. The LC50 values of F1 and F′1 strains were not significantly different and dominance values were 0.74 and 0.64, respectively. The resistance to Fipronil was completely recessive (DML = 0.00) at the highest dose and incompletely dominant at the lowest dose (DML = 0.87). The monogenic resistance based on chi-square goodness of fit test and calculation of the minimum number of segregating genes showed that resistance to Fipronil is controlled by multiple genes. The Fipronil resistance strain confirmed very low cross-resistance to emamectin benzoate and spinosad while no cross-resistance to chlorpyrifos and acetamiprid when compared to that of the field population. The heritability values were 0.112, 0.075, 0.084, 0.008, and 0.052 for Fipronil, emamectin benzoate, spinosad, acetamiprid, and chlorpyrifos, respectively. It was concluded that Fipronil resistance in M. domestica was autosomally inherited, incompletely dominant, and polygenic. These findings would be helpful for the better and successful management of M. domestica.
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cross resistance genetics and realized heritability of resistance to Fipronil in the house fly musca domestica diptera muscidae a potential vector for disease transmission
Parasitology Research, 2014Co-Authors: Naeem Abbas, Hafiz Azhar Ali Khan, Sarfraz Ali ShadAbstract:Houseflies, Musca domestica (L.), are ubiquitous pests that have the potential to spread a variety of pathogens to humans, poultries, and dairies. Pesticides are commonly used for the management of this pest. Fipronil is a GABA-gated chloride channel-inhibiting insecticide that has been commonly used for the management of different pests including M. domestica throughout the world. Many pests have developed resistance to this insecticide. A field-collected strain of M. domestica was selected with Fipronil for continuous 11 generations to assess the cross-resistance, genetics, and realized heritability for designing a resistance management strategy. Laboratory bioassays were performed using the feeding method of mixing insecticide concentrations with 20 % sugar solutions and cotton soaks dipped in insecticide solutions were provided to tested adult flies. Bioassay results at G12 showed that the Fipronil-selected strain developed a resistance ratio of 140-fold compared to the susceptible strain. Synergism bioassay with piperonyl butoxide (PBO) and S,S,S,-tributyl phosphorotrithioate (DEF) indicated that Fipronil resistance was associated with microsomal oxidase and also esterase. Reciprocal crosses between resistant and susceptible strains showed an autosomal and incompletely dominant resistance to Fipronil. The LC50 values of F1 and F′1 strains were not significantly different and dominance values were 0.74 and 0.64, respectively. The resistance to Fipronil was completely recessive (DML = 0.00) at the highest dose and incompletely dominant at the lowest dose (DML = 0.87). The monogenic resistance based on chi-square goodness of fit test and calculation of the minimum number of segregating genes showed that resistance to Fipronil is controlled by multiple genes. The Fipronil resistance strain confirmed very low cross-resistance to emamectin benzoate and spinosad while no cross-resistance to chlorpyrifos and acetamiprid when compared to that of the field population. The heritability values were 0.112, 0.075, 0.084, 0.008, and 0.052 for Fipronil, emamectin benzoate, spinosad, acetamiprid, and chlorpyrifos, respectively. It was concluded that Fipronil resistance in M. domestica was autosomally inherited, incompletely dominant, and polygenic. These findings would be helpful for the better and successful management of M. domestica.
Jay Z Yeh - One of the best experts on this subject based on the ideXlab platform.
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Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310(1
2020Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:ABSTRACT Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC 50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin
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glutamate activated chloride channels unique Fipronil targets present in insects but not in mammals
Pesticide Biochemistry and Physiology, 2010Co-Authors: Toshio Narahashi, Xilong Zhao, Vincent L Salgado, Tomoko Ikeda, Jay Z YehAbstract:Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of Fipronil. The IC(50)s of Fipronil block were 30 nM in cockroach GABA receptors and 1600 nM in rat GABA(A) receptors. Moreover, GluCls of cockroach neurons had low IC(50)s for Fipronil. Two types of glutamate-induced chloride current were obswerved: desensitizing and non-desensitizing, with Fipronil IC(50)s of 800 and 10 nM, respectively. We have developed methods to separately record these two types of GluCls. The non-desensitizing and desensitizing currents were selectively inhibited by trypsin and polyvinylpyrrolidone, respectively. In conclusion, in addition to GABA receptors, GluCls play a crucial role in selectivity of Fipronil to insects over mammals. GluCls form the basis for development of selective and safe insecticides.
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Fipronil is a potent open channel blocker of glutamate activated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.
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differential actions of Fipronil and dieldrin insecticides on gaba gated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to Fipronil and dieldrin. We examined differential actions of Fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas Fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of Fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.
Xilong Zhao - One of the best experts on this subject based on the ideXlab platform.
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Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310(1
2020Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:ABSTRACT Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC 50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin
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glutamate activated chloride channels unique Fipronil targets present in insects but not in mammals
Pesticide Biochemistry and Physiology, 2010Co-Authors: Toshio Narahashi, Xilong Zhao, Vincent L Salgado, Tomoko Ikeda, Jay Z YehAbstract:Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of Fipronil. The IC(50)s of Fipronil block were 30 nM in cockroach GABA receptors and 1600 nM in rat GABA(A) receptors. Moreover, GluCls of cockroach neurons had low IC(50)s for Fipronil. Two types of glutamate-induced chloride current were obswerved: desensitizing and non-desensitizing, with Fipronil IC(50)s of 800 and 10 nM, respectively. We have developed methods to separately record these two types of GluCls. The non-desensitizing and desensitizing currents were selectively inhibited by trypsin and polyvinylpyrrolidone, respectively. In conclusion, in addition to GABA receptors, GluCls play a crucial role in selectivity of Fipronil to insects over mammals. GluCls form the basis for development of selective and safe insecticides.
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Fipronil is a potent open channel blocker of glutamate activated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.
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differential actions of Fipronil and dieldrin insecticides on gaba gated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to Fipronil and dieldrin. We examined differential actions of Fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas Fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of Fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.
Vincent L Salgado - One of the best experts on this subject based on the ideXlab platform.
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Fipronil is a potent open channel blocker of glutamate-activated chloride channels in cockroach neurons. J Pharmacol Exp Ther 310(1
2020Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:ABSTRACT Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC 50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin
-
glutamate activated chloride channels unique Fipronil targets present in insects but not in mammals
Pesticide Biochemistry and Physiology, 2010Co-Authors: Toshio Narahashi, Xilong Zhao, Vincent L Salgado, Tomoko Ikeda, Jay Z YehAbstract:Selectivity to insects over mammals is one of the important characteristics for a chemical to become a useful insecticide. Fipronil was found to block cockroach GABA receptors more potently than rat GABA(A) receptors. Furthermore, glutamate-activated chloride channels (GluCls), which are present in cockroaches but not in mammals, were very sensitive to the blocking action of Fipronil. The IC(50)s of Fipronil block were 30 nM in cockroach GABA receptors and 1600 nM in rat GABA(A) receptors. Moreover, GluCls of cockroach neurons had low IC(50)s for Fipronil. Two types of glutamate-induced chloride current were obswerved: desensitizing and non-desensitizing, with Fipronil IC(50)s of 800 and 10 nM, respectively. We have developed methods to separately record these two types of GluCls. The non-desensitizing and desensitizing currents were selectively inhibited by trypsin and polyvinylpyrrolidone, respectively. In conclusion, in addition to GABA receptors, GluCls play a crucial role in selectivity of Fipronil to insects over mammals. GluCls form the basis for development of selective and safe insecticides.
-
Fipronil is a potent open channel blocker of glutamate activated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2004Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil, a phenylpyrazole insecticide, displays high insecticidal activity and reduced mammalian toxicity. To better elucidate the mechanism of its selective toxicity between insects and mammals and activity against dieldrin-resistant insects, we studied Fipronil action on glutamate-gated chloride channels (GluCls), unique invertebrate ligand-gated chloride channels, in cockroach thoracic ganglion neurons, using the whole-cell patch clamp technique. Glutamate evoked two types of chloride currents, a desensitizing current and a nondesensitizing current. Fipronil differentially inhibited these two types of currents with different potencies and with different rates of reversibility. Fipronil inhibited the desensitizing and nondesensitizing GluCls with IC50 values of 801 and 10 nM, respectively. Kinetic analysis revealed that Fipronil blocks required channel opening. Recovery of the desensitizing current from Fipronil block required channel opening, whereas recovery of nondesensitizing current from block was independent of channel opening. The high potency of Fipronil against the nondesensitizing current was due to a slow unblocking rate constant. In addition, when the nondesensitizing GluCls were occupied by picrotoxinin, the receptors became less sensitive to Fipronil block. It is concluded that GluCls are a critical target for Fipronil, especially for the selective toxicity between mammals and insects, and that Fipronil block of GluCls may play a role in the lack of the cross-resistance with dieldrin.
-
differential actions of Fipronil and dieldrin insecticides on gaba gated chloride channels in cockroach neurons
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Xilong Zhao, Jay Z Yeh, Vincent L Salgado, Toshio NarahashiAbstract:Fipronil and dieldrin are known to inhibit GABA receptors in both mammals and insects. However, the mechanism of selective toxicity of these insecticides between mammals and insects remains to be seen. One possible mechanism is that insect GABA receptors are more sensitive than mammalian GABAA receptors to Fipronil and dieldrin. We examined differential actions of Fipronil and dieldrin on GABA-gated chloride channels in insects and compared them with the data on mammalian GABAA receptors. Neurons were acutely dissociated from the American cockroach thoracic ganglia, and currents evoked by GABA were recorded by the whole-cell patch-clamp technique. GABA-evoked currents were carried by chloride ions, blocked by picrotoxinin, but not by bicuculline. Fipronil inhibited GABA currents with an IC50 value of 28 nM, whereas dieldrin exhibited a dual action potentiation with an EC50 value of 4 nM followed by inhibition with an IC50 value of 16 nM. Fipronil and dieldrin acted on the resting receptor at comparable rates, whereas Fipronil blocked the activated receptor 10 times faster than dieldrin. Fipronil inhibition was partially reversible, whereas dieldrin inhibition was irreversible. Fipronil was 59 times more potent on cockroach GABA receptors than on rat GABAA receptors. However, the potentiating and inhibitory potencies of dieldrin in cockroach GABA receptors were comparable with those in rat GABAA receptors. It was concluded that the higher toxicity of Fipronil in insects than in mammals is due partially to the higher sensitivity of GABA receptors. The mechanism of dieldrin's selective toxicity must lie in factors other than the sensitivity of GABA receptors.
