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Flumazenil-Insensitive Benzodiazepine Effects in Recombinant αβ and Neuronal GABAA Receptors
- Source :
- Brain Sciences, Vol 10, Iss 3, p 150 (2020)
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
Abstract
- Gamma-aminobutyric acid, type A (GABAA) receptors are complex heterogeneous pentamers with various drug binding sites. Several lines of evidence suggest that benzodiazepines modulate certain GABAA receptors in a flumazenil-insensitive manner, possibly via binding sites other than the classical ones. However, GABAA receptor subtypes that contain non-classical benzodiazepine binding sites are not systemically studied. The present study investigated the high-concentration effects of three benzodiazepines and their sensitivity to flumazenil on different recombinant (α1β2, α2β2, α3β2, α4β2, α5β2 and α1β3) and native neuronal GABAA receptors using the whole-cell patch-clamp electrophysiology technique. The classical benzodiazepine diazepam (200 μmol/L) and midazolam (200 μmol/L) produced flumazenil-insensitive effects on α1β2 receptor, whereas the imidazopyridine zolpidem failed to modulate the receptor. Flumazenil-insensitive effects of diazepam were also observed on the α2β2, α3β2 and α5β2, but not α4β2 receptors. Unlike β2-containing receptors, the α1β3 receptor was insensitive to diazepam. Moreover, the diazepam (200 μmol/L) effects on some cortical neurons could not be fully antagonized by flumazenil (200 μmol/L). These findings suggested that the non-classical (flumazenil-insensitive) benzodiazepine effects depended on certain receptor subtypes and benzodiazepine structures and may be important for designing of subtype- or binding site- specific drugs.
Details
- Language :
- English
- ISSN :
- 20763425
- Volume :
- 10
- Issue :
- 3
- Database :
- Directory of Open Access Journals
- Journal :
- Brain Sciences
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.fcb6e4af147c413e84acda27f2784cec
- Document Type :
- article
- Full Text :
- https://doi.org/10.3390/brainsci10030150