The Experts below are selected from a list of 186 Experts worldwide ranked by ideXlab platform
David B Sattelle - One of the best experts on this subject based on the ideXlab platform.
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blocking actions of bidn a bicyclic dinitrile convulsant compound on wild type and dieldrin resistant gaba receptor homo oligomers of drosophila melanogaster expressed in xenopus oocytes
Brain Research, 1995Co-Authors: A M Hosie, Yasuhito Shirai, Steven D. Buckingham, Howard A. Baylis, Richard T. Roush, James J Rauh, David B SattelleAbstract:The receptor antagonist actions are described for a novel bicyclic dinitrile compound (BIDN, 3,3-bis-(trifluoromethyl)-bicyclo [2.2.1] heptane-2,2-dicarbonitrile) on a Drosophila melanogaster homo-oligomeric GABA receptor expressed in Xenopus oocytes. BIDN blocked the wild-type form of the receptor in a neither purely competitive, nor purely non-competitive manner, being dependent on the GABA concentration yet insurmountable, and block was independent of the membrane potential. BIDN was found to be less effective against a mutant (A(302) --> S) form of the receptor resistant to dieldrin and Picrotoxinin. This cross resistance of dieldrin-resistant receptors to BIDN is of interest in the light of recent findings that BIDN binding to insect membranes is displaced competitively by dieldrin, but not by Picrotoxinin.
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Actions of Picrotoxinin analogues on an expressed, homo-oligomeric GABA receptor of Drosophila melanogaster
Neuroscience letters, 1995Co-Authors: Yasuhito Shirai, Caleb William Holyoke, Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:The actions of Picrotoxinin and four of its analogues were tested on a Drosophila melanogaster homo-oligomeric GABA (gamma-aminobutyric acid) receptor formed when RDL (resistance to dieldrin) subunits were expressed in Xenopus oocytes. In agreement with previously reported studies on native insect GABA receptors and native expressed vertebrate GABA receptors, acetylation of the bridgehead hydroxyl group (Picrotoxinin acetate) greatly reduced the activity of the molecule, but surprisingly, substitution with flourine at the same position also reduced the activity. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity, in agreement with findings for native insect and mammalian receptors. The present results suggest that interactions of convulsants with homo-oligomeric and multimeric GABA receptors are qualitatively similar. Thus, the RDL homo-oligomer exhibits a pharmacological profile for Picrotoxinin analogues resembling that of native GABA receptors.
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Actions of the insecticide fipronil, on dieldrin-sensitive and- resistant GABA receptors of Drosophila melanogaster.
British journal of pharmacology, 1995Co-Authors: Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:1. Blocking actions of the novel insecticide, fipronil, were examined on GABA responses recorded from Xenopus oocytes expressing either wild type (dieldrin-sensitive) or mutant (dieldrin-resistant) forms of the Drosophila melanogaster GABA-gated chloride channel homo-oligomer, RDL (the product of the resistance to dieldrin locus: Rdl). 2. In the case of the wild type receptor, fipronil blocked GABA-induced currents inducing both a shift to the right in the GABA dose-response curve and depressing the maximum amplitude of responses to GABA. The potency of fipronil was dependent on the GABA concentration but was unaffected by membrane potential. 3. Mutant RDL GABA-receptors, which have a naturally occurring amino acid substitution (A302-->S) in the putative ion-channel lining region, conferring resistance to dieldrin and Picrotoxinin, were markedly less sensitive to fipronil than the wild-type receptors. 4. Fipronil antagonism is qualitatively similar to that produced by the structurally distinct compound, Picrotoxinin. As the mutation A302-->S reduces the potency of both fipronil and Picrotoxinin, homooligomeric RDL receptors should facilitate detailed studies of the molecular basis of convulsant/insecticide antagonist actions on GABA receptors.
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blocking actions of Picrotoxinin analogues on insect periplaneta americana gaba receptors
Neuroscience Letters, 1994Co-Authors: N M Anthony, Caleb William Holyoke, David B SattelleAbstract:Five Picrotoxinin analogues were examined on GABA-gated chloride channels of an identifiable cockroach (Periplaneta americana) motor neurone (Df). Substitution of the bridgehead hydroxyl at the C-6 position of the Picrotoxinin molecule by a fluorine atom (fluoroPicrotoxinin) had little effect, whereas acetylation of the same functional group (Picrotoxinin acetate) substantially reduced the effectiveness of the parent compound. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity. Dendrobine, a naturally-occurring Picrotoxinin-like compound had very little effect on GABA-induced responses at concentrations up to 1.0 x 10(-5) M. The present results suggest that the size and the ability of the bridgehead hydroxyl to undergo hydrogen bond formation and the lipophilic nature of the terminal isopropenyl group profoundly affect the inhibitory actions of the Picrotoxinin molecule on insect neuronal GABA-gated chloride channels.
Graham A.r. Johnston - One of the best experts on this subject based on the ideXlab platform.
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Effects of bilobalide, ginkgolide B and Picrotoxinin on GABAA receptor modulation by structurally diverse positive modulators.
European journal of pharmacology, 2017Co-Authors: Rujee K. Duke, Tina Hinton, Graham A.r. JohnstonAbstract:Anxiolytics and anticonvulsants generally positively modulate the action of GABA, whereas many convulsants (including the chloride channel blocker Picrotoxinin) negatively modulate the action of GABA on GABAA receptors. Like Picrotoxinin, bilobalide and ginkgolide B, active constituents of Ginkgo biloba, have been shown to negatively modulate the action of GABA at α1β2γ2L GABAA receptors. However, unlike Picrotoxinin, bilobalide and ginkgolide B are not known to cause convulsions. We have assessed the action of bilobalide, ginkgolide B and Picrotoxinin on a range of GABAA modulators (etomidate, loreclezole, propofol, thiopentone sodium, diazepam, and allopregnanolone), using two-electrode voltage clamp electrophysiology at recombinant α1β2γ2L GABAA receptors expressed in Xenopus oocytes. The results indicate that bilobalide and ginkgolide B differ from Picrotoxinin in their ability to inhibit the actions of a range of these structurally diverse GABAA positive modulators consistent with these modulators acting on a multiplicity of active sites associated with GABAA receptors. In the presence GABA, ginkgolide B was more potent than bilobalide in inhibiting the GABA-potentiating effect of propofol, equipotent against loreclezole and allopregnanolone, and less potent against etomidate, diazepam, and thiopentone sodium. This indicates that in comparison to Picrotoxinin, bilobalide and ginkgolide B differ in their effects on the different modulators.
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GABAA receptor cysteinyl mutants and the ginkgo terpenoid lactones bilobalide and ginkgolides
European Journal of Pharmacology, 2016Co-Authors: Chiu Chin Ng, Rujee K. Duke, Tina Hinton, Graham A.r. JohnstonAbstract:The terpenoid lactones from Ginkgo biloba, bilobalide and ginkgolides, have been shown to act as negative modulators at α1β2γ2L GABAA receptors. They have structural features similar to those of the chloride channel blocker Picrotoxinin. Unlike Picrotoxinin, however they are not known to produce convulsant effects. Using two-electrode voltage clamp electrophysiology, this study compared the effect of mutation of 2', 6' and 15' pore facing M2 domain residues to cysteine on the action of Picrotoxinin, bilobalide and ginkgolides at α1β2γ2L GABAA receptors expressed in Xenopus oocytes. Picrotoxinin was affected by mutation differently from the ginkgo terpenoid lactones. Although some of these compounds were affected by the mutation at same position and/or subunit, the changes in their potency were found to be dissimilar. The results suggest that the intracellular pore binding site for Picrotoxinin, bilobalide, ginkgolide A, ginkgolide B and ginkgolide C is comprised of 2'β-6'β6'γ, 2'α2'β-6'α6'β, 2'α2'β2'γ-6'β6'γ, 2'α, 2'β2'γ-6'β and 2'α2'β, respectively. Unlike bilobalide and ginkgolides, the inhibitory action of Picrotoxinin was not affected by mutations at 15' position. It is proposed that 15'α15'β, 15'β, 15'α15'β and 15'α15'β15'γ forms an extracellular pore binding site for bilobalide, ginkgolide A, ginkgolide B and ginkgolide C, respectively. The lack of convulsant effects of bilobalide, and ginkgolide A and B may be associated in part with their different binding locations within the chloride channel.
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Relative impact of residues at the intracellular and extracellular ends of the human GABAC ρ1 receptor M2 domain on Picrotoxinin activity
European Journal of Pharmacology, 2007Co-Authors: Jane E. Carland, Graham A.r. Johnston, Mary ChebibAbstract:Abstract The relative impact on Picrotoxinin activity of residues at the intracellular (2′ and 6′ residues) and extracellular (15′ and 17′ residues) ends of the second transmembrane (M2) domain of the human γ-aminobutyric acid-C (GABA C ) ρ1 receptor was investigated. A series of GABA C ρ1 subunits were produced containing either single or multiple mutations at the positions of interest. Wild-type and mutant subunits (containing one or more of the following mutations: P2′S, T6′M, I15′N, G17′H) were expressed in Xenopus oocytes and characterized using agonists, partial agonists and antagonists. Changes in agonist activity were observed for mutant receptors. Most notably, mutation at the 2′ position resulted in decreased agonist potency, while mutation at the 15′ and 17′ residues increased agonist potency. The affinity of the competitive antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) was unchanged compared to wild-type at all mutant receptors. Of the four residues studied, mutation of residues at the 2′ and 6′ positions had the greatest impact on Picrotoxinin activity. Inclusion of the P2′S mutation typically produced receptors with increased Picrotoxinin potency, while the T6′M mutation reduced Picrotoxinin potency. Picrotoxinin is a mixed antagonist at wild-type and all mutant receptors, with the exception of the double mutant ρ1P2′S/T6′M receptors at which the non-competitive component was isolated. It is proposed that the contribution of M2 domain residues to Picrotoxinin activity is potentially two-fold: (1) their role as a potential Picrotoxinin binding site within the pore; and (2) they are critical for receptor activation properties of the receptor, thus may alter the allosteric mechanism of Picrotoxinin.
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Relative impact of residues at the intracellular and extracellular ends of the human GABAC rho1 receptor M2 domain on Picrotoxinin activity.
European journal of pharmacology, 2007Co-Authors: Jane E. Carland, Graham A.r. Johnston, Mary ChebibAbstract:The relative impact on Picrotoxinin activity of residues at the intracellular (2' and 6' residues) and extracellular (15' and 17' residues) ends of the second transmembrane (M2) domain of the human gamma-aminobutyric acid-C (GABA(C)) rho1 receptor was investigated. A series of GABA(C) rho1 subunits were produced containing either single or multiple mutations at the positions of interest. Wild-type and mutant subunits (containing one or more of the following mutations: P2'S, T6'M, I15'N, G17'H) were expressed in Xenopus oocytes and characterized using agonists, partial agonists and antagonists. Changes in agonist activity were observed for mutant receptors. Most notably, mutation at the 2' position resulted in decreased agonist potency, while mutation at the 15' and 17' residues increased agonist potency. The affinity of the competitive antagonist (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid (TPMPA) was unchanged compared to wild-type at all mutant receptors. Of the four residues studied, mutation of residues at the 2' and 6' positions had the greatest impact on Picrotoxinin activity. Inclusion of the P2'S mutation typically produced receptors with increased Picrotoxinin potency, while the T6'M mutation reduced Picrotoxinin potency. Picrotoxinin is a mixed antagonist at wild-type and all mutant receptors, with the exception of the double mutant rho1P2'S/T6'M receptors at which the non-competitive component was isolated. It is proposed that the contribution of M2 domain residues to Picrotoxinin activity is potentially two-fold: (1) their role as a potential Picrotoxinin binding site within the pore; and (2) they are critical for receptor activation properties of the receptor, thus may alter the allosteric mechanism of Picrotoxinin.
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Bilobalide, a sesquiterpene trilactone from Ginkgo biloba, is an antagonist at recombinant α1β2γ2L GABAA receptors
European journal of pharmacology, 2003Co-Authors: Shelley H. Huang, Rujee K. Duke, Keiko Sasaki, Keiji Wada, Mary Chebib, Graham A.r. JohnstonAbstract:Abstract The sesquiterpene trilactone bilobalide is one of the active constituents of the 50:1 Ginkgo biloba leaf extract widely used to enhance memory and learning. Bilobalide was found to antagonise the direct action of γ-aminobutyric acid (GABA) on recombinant α1β2γ2L GABAA receptors. The effect of bilobalide on the direct action of GABA at α1β2γ2L GABAA receptors expressed in Xenopus laevis oocytes using two-electrode voltage-clamp method was evaluated and compared with the effects of the classical GABAA receptor competitive antagonist bicuculline and noncompetitive antagonist Picrotoxinin. Bilobalide (IC50=4.6±0.5 μM) was almost as potent as bicuculline and pictrotoxinin (IC50=2.0±0.1 and 2.4±0.5 μM, respectively) at α1β2γ2L GABAA receptors against 40 μM GABA (GABA EC50). While bilobalide and Picrotoxinin were clearly noncompetitive antagonists, the potency of bilobalide decreased at high GABA concentrations suggesting a component of competitive antagonism.
Richard H. Ffrench-constant - One of the best experts on this subject based on the ideXlab platform.
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Expression of a Drosophila GABA receptor in a baculovirus insect cell system: Functional expression of insecticide susceptible and resistant GABA receptors from the cyclodiene resistance gene Rdl
FEBS letters, 1993Co-Authors: Hwa-jung Lee, Thomas A. Rocheleau, Hai-guang Zhang, Meyer B. Jackson, Richard H. Ffrench-constantAbstract:Recombinant baculoviruses containing two alternative splice forms of the Drosophila Rdl GABA receptor gene were constructed. Spodoptera frugiperda (Sf21) cells infected with either splice form expressed a transcript of expected size (2.5 kb). Western blotting of cell membrane extracts and immunoprecipitation experiments with an anti-Rdl antiserum recognized a protein of the expected size of ~65 kDa. Whole cell patch clamp analysis of cells infected with either splice form revealed functional expression of GABA gated chloride ion channels which were blocked by application of 1 μM Picrotoxinin. Following replacement of alanine 302 with a serine, a mutation associated with resistance to Picrotoxinin and cyclodiene insecticides, mutant channels showed similar levels of insensitivity to Picrotoxinin (~ 100-fold) as those observed in recordings from cultured Drosophila neurons. The significance of the expression of an insect GABA receptor in an insect cell line and the similarity of the results from these functional expression studies to recordings from cultured neurons is discussed.
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Reduced neuronal sensitivity to dieldrin and Picrotoxinin in a cyclodiene‐resistant strain of Drosophila melanogaster (Meigen)
Archives of insect biochemistry and physiology, 1992Co-Authors: Jeffrey R. Bloomquist, Richard T. Roush, Richard H. Ffrench-constantAbstract:Toxicological and neurophysiological studies were performed to characterize the resistance mechanism in a cyclodiene-resistant strain of Drosophila melanogaster (Maryland strain). Dieldrin had an LC50 of 0.058 ppm against the larvae of susceptible D. melanogaster (Oregon-R wild type) when formulated in the rearing media. The LC50 of the resistant Maryland strain was 10.8 ppm, giving a resistance ratio (LC50-Maryland/LC50-susceptible) of 186-fold. Suction electrode recordings were made from peripheral nerves of the larval central nervous system to test whether reduced nerve sensitivity played any role in the observed resistance. In susceptible preparations (n = 5), inhibition of nerve firing by 1 mM gamma-aminobutyric acid (GABA) was effectively antagonized within 3-10 min by 10 microM dieldrin. In contrast, 30 min incubations with 10 microM dieldrin had no effect on preparations from cyclodiene-resistant individuals (n = 5). Similarly, 10 microM Picrotoxinin blocked GABA-dependent inhibition in susceptible nerve preparations (n = 3). In recordings from resistant insects (n = 4), Picrotoxinin displayed either weak antagonism of GABA or hyperexcitation indistinguishable from susceptible preparations. These results demonstrate that cyclodiene resistance in the Maryland strain of D. melanogaster 1) is expressed in immature stages, 2) is present at the level of the nerve, and 3) extends to Picrotoxinin, albeit at a reduced level compared with dieldrin. The possible role of an altered GABA receptor in this resistance is discussed.
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Excitation of central neurons by dieldrin and Picrotoxinin in susceptible and resistant Drosophila melanogaster (meigen)
Pesticide Science, 1991Co-Authors: Jeffrey R. Bloomquist, Richard H. Ffrench-constant, Richard T. RoushAbstract:Neurophysiological studies were used to characterize the resistance mechanism in a new cyclodiene-resistant strain of Drosophila melanogaster. Suction electrode recordings were taken from the peripheral nerves of transected larval central nervous system. Treatment of nerve preparations with 1 mM GABA reduced the spontaneous firing of peripheral nerves. This inhibition was effectively reversed within 10 min by exposing preparations from susceptible insects (Oregon-R wild type) to 10 μM dieldrin. In contrast, 30 min incubations with 10 μM dieldrin had no effect on preparations from resistant individuals. At 10 μM, Picrotoxinin was also effective in antagonizing the action of GABA in susceptible nerve preparations. In recordings from resistant insects (n = 3), Picrotoxinin displayed either no antagonism of GABA-dependent inhibition, weak antagonism of GABA, or hyperexcitation indistinguishable from those of susceptible preparations. These results demonstrate that cyclodiene resistance in the Maryland strain of D. melanogaster is present at the level of the nerve, and that the resistance extends to Picrotoxinin, albeit at a reduced level. The possible role of an altered GABA receptor in this resistance is discussed.
Steven D. Buckingham - One of the best experts on this subject based on the ideXlab platform.
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blocking actions of bidn a bicyclic dinitrile convulsant compound on wild type and dieldrin resistant gaba receptor homo oligomers of drosophila melanogaster expressed in xenopus oocytes
Brain Research, 1995Co-Authors: A M Hosie, Yasuhito Shirai, Steven D. Buckingham, Howard A. Baylis, Richard T. Roush, James J Rauh, David B SattelleAbstract:The receptor antagonist actions are described for a novel bicyclic dinitrile compound (BIDN, 3,3-bis-(trifluoromethyl)-bicyclo [2.2.1] heptane-2,2-dicarbonitrile) on a Drosophila melanogaster homo-oligomeric GABA receptor expressed in Xenopus oocytes. BIDN blocked the wild-type form of the receptor in a neither purely competitive, nor purely non-competitive manner, being dependent on the GABA concentration yet insurmountable, and block was independent of the membrane potential. BIDN was found to be less effective against a mutant (A(302) --> S) form of the receptor resistant to dieldrin and Picrotoxinin. This cross resistance of dieldrin-resistant receptors to BIDN is of interest in the light of recent findings that BIDN binding to insect membranes is displaced competitively by dieldrin, but not by Picrotoxinin.
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Actions of Picrotoxinin analogues on an expressed, homo-oligomeric GABA receptor of Drosophila melanogaster
Neuroscience letters, 1995Co-Authors: Yasuhito Shirai, Caleb William Holyoke, Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:The actions of Picrotoxinin and four of its analogues were tested on a Drosophila melanogaster homo-oligomeric GABA (gamma-aminobutyric acid) receptor formed when RDL (resistance to dieldrin) subunits were expressed in Xenopus oocytes. In agreement with previously reported studies on native insect GABA receptors and native expressed vertebrate GABA receptors, acetylation of the bridgehead hydroxyl group (Picrotoxinin acetate) greatly reduced the activity of the molecule, but surprisingly, substitution with flourine at the same position also reduced the activity. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity, in agreement with findings for native insect and mammalian receptors. The present results suggest that interactions of convulsants with homo-oligomeric and multimeric GABA receptors are qualitatively similar. Thus, the RDL homo-oligomer exhibits a pharmacological profile for Picrotoxinin analogues resembling that of native GABA receptors.
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Actions of the insecticide fipronil, on dieldrin-sensitive and- resistant GABA receptors of Drosophila melanogaster.
British journal of pharmacology, 1995Co-Authors: Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:1. Blocking actions of the novel insecticide, fipronil, were examined on GABA responses recorded from Xenopus oocytes expressing either wild type (dieldrin-sensitive) or mutant (dieldrin-resistant) forms of the Drosophila melanogaster GABA-gated chloride channel homo-oligomer, RDL (the product of the resistance to dieldrin locus: Rdl). 2. In the case of the wild type receptor, fipronil blocked GABA-induced currents inducing both a shift to the right in the GABA dose-response curve and depressing the maximum amplitude of responses to GABA. The potency of fipronil was dependent on the GABA concentration but was unaffected by membrane potential. 3. Mutant RDL GABA-receptors, which have a naturally occurring amino acid substitution (A302-->S) in the putative ion-channel lining region, conferring resistance to dieldrin and Picrotoxinin, were markedly less sensitive to fipronil than the wild-type receptors. 4. Fipronil antagonism is qualitatively similar to that produced by the structurally distinct compound, Picrotoxinin. As the mutation A302-->S reduces the potency of both fipronil and Picrotoxinin, homooligomeric RDL receptors should facilitate detailed studies of the molecular basis of convulsant/insecticide antagonist actions on GABA receptors.
Howard A. Baylis - One of the best experts on this subject based on the ideXlab platform.
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blocking actions of bidn a bicyclic dinitrile convulsant compound on wild type and dieldrin resistant gaba receptor homo oligomers of drosophila melanogaster expressed in xenopus oocytes
Brain Research, 1995Co-Authors: A M Hosie, Yasuhito Shirai, Steven D. Buckingham, Howard A. Baylis, Richard T. Roush, James J Rauh, David B SattelleAbstract:The receptor antagonist actions are described for a novel bicyclic dinitrile compound (BIDN, 3,3-bis-(trifluoromethyl)-bicyclo [2.2.1] heptane-2,2-dicarbonitrile) on a Drosophila melanogaster homo-oligomeric GABA receptor expressed in Xenopus oocytes. BIDN blocked the wild-type form of the receptor in a neither purely competitive, nor purely non-competitive manner, being dependent on the GABA concentration yet insurmountable, and block was independent of the membrane potential. BIDN was found to be less effective against a mutant (A(302) --> S) form of the receptor resistant to dieldrin and Picrotoxinin. This cross resistance of dieldrin-resistant receptors to BIDN is of interest in the light of recent findings that BIDN binding to insect membranes is displaced competitively by dieldrin, but not by Picrotoxinin.
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Actions of Picrotoxinin analogues on an expressed, homo-oligomeric GABA receptor of Drosophila melanogaster
Neuroscience letters, 1995Co-Authors: Yasuhito Shirai, Caleb William Holyoke, Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:The actions of Picrotoxinin and four of its analogues were tested on a Drosophila melanogaster homo-oligomeric GABA (gamma-aminobutyric acid) receptor formed when RDL (resistance to dieldrin) subunits were expressed in Xenopus oocytes. In agreement with previously reported studies on native insect GABA receptors and native expressed vertebrate GABA receptors, acetylation of the bridgehead hydroxyl group (Picrotoxinin acetate) greatly reduced the activity of the molecule, but surprisingly, substitution with flourine at the same position also reduced the activity. Conversion of the terminal isopropenyl group to an acetyl (alpha-picrotoxinone) or hydration of the double bond (picrotin) also reduced activity, in agreement with findings for native insect and mammalian receptors. The present results suggest that interactions of convulsants with homo-oligomeric and multimeric GABA receptors are qualitatively similar. Thus, the RDL homo-oligomer exhibits a pharmacological profile for Picrotoxinin analogues resembling that of native GABA receptors.
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Actions of the insecticide fipronil, on dieldrin-sensitive and- resistant GABA receptors of Drosophila melanogaster.
British journal of pharmacology, 1995Co-Authors: Alastair M. Hosie, Steven D. Buckingham, Howard A. Baylis, David B SattelleAbstract:1. Blocking actions of the novel insecticide, fipronil, were examined on GABA responses recorded from Xenopus oocytes expressing either wild type (dieldrin-sensitive) or mutant (dieldrin-resistant) forms of the Drosophila melanogaster GABA-gated chloride channel homo-oligomer, RDL (the product of the resistance to dieldrin locus: Rdl). 2. In the case of the wild type receptor, fipronil blocked GABA-induced currents inducing both a shift to the right in the GABA dose-response curve and depressing the maximum amplitude of responses to GABA. The potency of fipronil was dependent on the GABA concentration but was unaffected by membrane potential. 3. Mutant RDL GABA-receptors, which have a naturally occurring amino acid substitution (A302-->S) in the putative ion-channel lining region, conferring resistance to dieldrin and Picrotoxinin, were markedly less sensitive to fipronil than the wild-type receptors. 4. Fipronil antagonism is qualitatively similar to that produced by the structurally distinct compound, Picrotoxinin. As the mutation A302-->S reduces the potency of both fipronil and Picrotoxinin, homooligomeric RDL receptors should facilitate detailed studies of the molecular basis of convulsant/insecticide antagonist actions on GABA receptors.