Benzodiazepine modulation of the rat GABAA receptor α4β3γ2L subtype expressed in Xenopus oocytes

Neuropharmacology
Haitao YouSusan M J Dunn

Abstract

The effects of benzodiazepines on GABA(A) receptors are dependent largely on the particular α subunit isoform that is present in the receptor pentamer. The inclusion of either the α4 or α6 subunit is generally thought to render the receptor insensitive to classical benzodiazepines. We expressed the rat α4β3γ2L subtype in Xenopus oocytes and observed that both diazepam and flunitrazepam significantly potentiated GABA-gated currents. This potentiation occurred at nanomolar concentrations similar to those seen at the most abundant "diazepam-sensitive" receptor i.e., the α1β2γ2 subtype. In the α4β3γ2L receptor, the effects of diazepam and flunitrazepam were inhibited by nanomolar concentrations of the benzodiazepine site antagonists, Ro15-1788 and ZK93426. The presence of the β3 subunit appears to be important for this modulation since diazepam did not affect GABA responses mediated by recombinant α4β1γ2L or α4β2γ2L receptors. Interestingly, when the α4β3γ2L receptor was expressed in HEK293 cells, diazepam and flunitrazepam displaced the relatively non-selective benzodiazepine site ligand, [(3)H]Ro15-4513, only at high concentrations (>10 μM) demonstrating a lack of high affinity binding for these classical benzodiazepines. Functio...Continue Reading

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Citations

Apr 13, 2012·Canadian Journal of Physiology and Pharmacology·Janna L Kozuska, Isabelle M Paulsen
Feb 18, 2014·British Journal of Pharmacology·Stephen P H AlexanderUNKNOWN CGTP Collaborators
Feb 3, 2021·Food & Function·Zeeshan HafeezLaurent Miclo
May 7, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·César MatteiChristian Legros

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