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Barbiturate interactions at the human GABA A receptor: dependence on receptor subunit combination

Barbiturate interactions at the human GABA A receptor: dependence on receptor subunit combination 1 Human GABAA receptors containing different α and β subunits with a γ2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two‐electrode voltage‐clamp method. 2 Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. In this study pentobarbitone activity consisted of the above mentioned three components on all the subunit combinations tested. However, the affinities and efficacies varied with receptor subtype. 3 Potentiation of GABA by pentobarbitone occurred over the same concentration‐range for all the subunits with affinities in the range of 20–35 μm. The degree of potentiation obtained, however, varied from 236% of GABA EC20 on α1β2γ2s to 536% on α6β2γ2s. 4 Examination of the direct effect of pentobarbitone revealed that the type of α subunit present determines both the degree of affinity and efficacy obtained. Receptors containing an α6 subunit produced maximum direct responses to pentobarbitone larger than that obtainable with maximum GABA (150% to 170% of maximum GABA). The maximum direct pentobarbitone response obtainable with other α subunits ranged between 45% of maximum GABA for α5β2γ2s to 82% for α2β2γ2s. The affinity of the direct action of pentobarbitone on α6β2γ2s was 58 μm compared to affinities for the other α subunits ranging from 139 μm on α2β2γ2s to 528 μm on α5β2γ2s. 5 The type of β subunit present did not influence the direct action of pentobarbitone to the same extent as the α subunit. There were no significant differences between affinity or efficacy on oocytes expressing α6 and γ2s with β1, β2 or β3. Affinities and efficacies on oocytes expressing α1 and γ2s with β1, β2 or β3 were significantly different with pentobarbitone having a higher affinity and efficacy on α1β3γ2s followed by α1β2γ2s and then α1β1γ2s. 6 The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7 For the first time the influence of the various α and β subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing α6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Pharmacology Wiley

Barbiturate interactions at the human GABA A receptor: dependence on receptor subunit combination

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References (50)

Publisher
Wiley
Copyright
1996 British Pharmacological Society
ISSN
0007-1188
eISSN
1476-5381
DOI
10.1111/j.1476-5381.1996.tb15221.x
Publisher site
See Article on Publisher Site

Abstract

1 Human GABAA receptors containing different α and β subunits with a γ2s subunit were expressed in Xenopus oocytes and the effects of pentobarbitone on these subunit combinations were examined by electrophysiological recording of GABA currents with the two‐electrode voltage‐clamp method. 2 Pentobarbitone has previously been shown to have three actions on GABAA receptors: a potentiation of GABA responses, a direct activation of GABAA receptors and, at high concentrations, a block of the GABA chloride channel. In this study pentobarbitone activity consisted of the above mentioned three components on all the subunit combinations tested. However, the affinities and efficacies varied with receptor subtype. 3 Potentiation of GABA by pentobarbitone occurred over the same concentration‐range for all the subunits with affinities in the range of 20–35 μm. The degree of potentiation obtained, however, varied from 236% of GABA EC20 on α1β2γ2s to 536% on α6β2γ2s. 4 Examination of the direct effect of pentobarbitone revealed that the type of α subunit present determines both the degree of affinity and efficacy obtained. Receptors containing an α6 subunit produced maximum direct responses to pentobarbitone larger than that obtainable with maximum GABA (150% to 170% of maximum GABA). The maximum direct pentobarbitone response obtainable with other α subunits ranged between 45% of maximum GABA for α5β2γ2s to 82% for α2β2γ2s. The affinity of the direct action of pentobarbitone on α6β2γ2s was 58 μm compared to affinities for the other α subunits ranging from 139 μm on α2β2γ2s to 528 μm on α5β2γ2s. 5 The type of β subunit present did not influence the direct action of pentobarbitone to the same extent as the α subunit. There were no significant differences between affinity or efficacy on oocytes expressing α6 and γ2s with β1, β2 or β3. Affinities and efficacies on oocytes expressing α1 and γ2s with β1, β2 or β3 were significantly different with pentobarbitone having a higher affinity and efficacy on α1β3γ2s followed by α1β2γ2s and then α1β1γ2s. 6 The direct effect of pentobarbitone was blocked by picrotoxin but not by competitive antagonists, such as bicuculline or SR95531, indicating that the direct agonist activity of pentobarbitone was not mediated via the GABA binding site. 7 For the first time the influence of the various α and β subunits on the effects of pentobarbitone were demonstrated. The results indicate that GABAA receptors containing α6 subunits have both a higher affinity and efficacy for direct activation by pentobarbitone, and reveal that pentobarbitone binds to more than one site on the GABAA receptor, and these are dependent on receptor subunit composition.

Journal

British Journal of Pharmacology – Wiley

Published: Feb 1, 1996

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