Effects of γ-HCH and δ-HCH on human recombinant GABAA receptors

dependence on GABAA receptor subunit combination

P. D. Maskell, K. A. Wafford, I. Bermudez*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

1. Human GABAA receptors containing different α and β subunits with or without the γ2S or γ2L subunits were expressed in Xenopus oocytes and the effects of the insecticides γ- and δ-hexachlorocyclohexane (γ-HCH and δ-HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage-clamp procedures. 2. δ-HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1-1.9 μM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in β1-containing receptors. 3. δ-HCH both potentiated GABA A receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABA A receptor function by δ-HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of δ-HCH were abolished in receptors containing either α4, β1 or γ2L subunits. 4. Sensitivity to the direct actions were not restored in receptors containing the mutant β1(S290N) subunit, but α1β2γ2L receptors became sensitive to the direct actions of δ-HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl-2-methyl piperazine dihydrochloride (H-7). 5. We have shown the influence of various α, β and γ subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of δ-HCH nor the allosteric effects δ-HCH ha a strict subunit dependency. By contrast, sensitivity to the direct actions of δ-HCH are abolished in receptors containing α4, β1 or γ2L subunits.

Original languageEnglish
Pages (from-to)205-212
Number of pages8
JournalBritish Journal of Pharmacology
Volume132
Issue number1
DOIs
Publication statusPublished - 2001
Externally publishedYes

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GABA-A Receptors
gamma-Aminobutyric Acid
Oocytes
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
Lindane
Protein Kinase Inhibitors
Insecticides
Xenopus
Electrodes

Cite this

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title = "Effects of γ-HCH and δ-HCH on human recombinant GABAA receptors: dependence on GABAA receptor subunit combination",
abstract = "1. Human GABAA receptors containing different α and β subunits with or without the γ2S or γ2L subunits were expressed in Xenopus oocytes and the effects of the insecticides γ- and δ-hexachlorocyclohexane (γ-HCH and δ-HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage-clamp procedures. 2. δ-HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1-1.9 μM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in β1-containing receptors. 3. δ-HCH both potentiated GABA A receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABA A receptor function by δ-HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of δ-HCH were abolished in receptors containing either α4, β1 or γ2L subunits. 4. Sensitivity to the direct actions were not restored in receptors containing the mutant β1(S290N) subunit, but α1β2γ2L receptors became sensitive to the direct actions of δ-HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl-2-methyl piperazine dihydrochloride (H-7). 5. We have shown the influence of various α, β and γ subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of δ-HCH nor the allosteric effects δ-HCH ha a strict subunit dependency. By contrast, sensitivity to the direct actions of δ-HCH are abolished in receptors containing α4, β1 or γ2L subunits.",
author = "Maskell, {P. D.} and Wafford, {K. A.} and I. Bermudez",
year = "2001",
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Effects of γ-HCH and δ-HCH on human recombinant GABAA receptors : dependence on GABAA receptor subunit combination. / Maskell, P. D.; Wafford, K. A.; Bermudez, I.

In: British Journal of Pharmacology, Vol. 132, No. 1, 2001, p. 205-212.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effects of γ-HCH and δ-HCH on human recombinant GABAA receptors

T2 - dependence on GABAA receptor subunit combination

AU - Maskell, P. D.

AU - Wafford, K. A.

AU - Bermudez, I.

PY - 2001

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N2 - 1. Human GABAA receptors containing different α and β subunits with or without the γ2S or γ2L subunits were expressed in Xenopus oocytes and the effects of the insecticides γ- and δ-hexachlorocyclohexane (γ-HCH and δ-HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage-clamp procedures. 2. δ-HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1-1.9 μM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in β1-containing receptors. 3. δ-HCH both potentiated GABA A receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABA A receptor function by δ-HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of δ-HCH were abolished in receptors containing either α4, β1 or γ2L subunits. 4. Sensitivity to the direct actions were not restored in receptors containing the mutant β1(S290N) subunit, but α1β2γ2L receptors became sensitive to the direct actions of δ-HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl-2-methyl piperazine dihydrochloride (H-7). 5. We have shown the influence of various α, β and γ subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of δ-HCH nor the allosteric effects δ-HCH ha a strict subunit dependency. By contrast, sensitivity to the direct actions of δ-HCH are abolished in receptors containing α4, β1 or γ2L subunits.

AB - 1. Human GABAA receptors containing different α and β subunits with or without the γ2S or γ2L subunits were expressed in Xenopus oocytes and the effects of the insecticides γ- and δ-hexachlorocyclohexane (γ-HCH and δ-HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage-clamp procedures. 2. δ-HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1-1.9 μM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in β1-containing receptors. 3. δ-HCH both potentiated GABA A receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABA A receptor function by δ-HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of δ-HCH were abolished in receptors containing either α4, β1 or γ2L subunits. 4. Sensitivity to the direct actions were not restored in receptors containing the mutant β1(S290N) subunit, but α1β2γ2L receptors became sensitive to the direct actions of δ-HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl-2-methyl piperazine dihydrochloride (H-7). 5. We have shown the influence of various α, β and γ subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of δ-HCH nor the allosteric effects δ-HCH ha a strict subunit dependency. By contrast, sensitivity to the direct actions of δ-HCH are abolished in receptors containing α4, β1 or γ2L subunits.

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DO - 10.1038/sj.bjp.0703824

M3 - Article

VL - 132

SP - 205

EP - 212

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

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