Flumazenil-Insensitive Benzodiazepine Effects in Recombinant ?? and Neuronal GABAA Receptors.

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 (?1?2, ?2?2, ?3?2, ?4?2, ?5?2 and ?1?3) and native neuronal GABAA receptors using the whole-cell patch-clamp electrophysiology technique. The classical benzodiazepine diazepam (200 ?mol/L) and midazolam (200 ?mol/L) produced flumazenil-insensitive effects on ?1?2 receptor, whereas the imidazopyridine zolpidem failed to modulate the receptor. Flumazenil-insensitive effects of diazepam were also observed on the ?2?2, ?3?2 and ?5?2, but not ?4?2 receptors. Unlike ?2-containing receptors, the ?1?3 receptor was insensitive to diazepam. Moreover, the diazepam (200 ?mol/L) effects on some cortical neurons could not be fully antagonized by flumazenil (200 ?mol/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.

SUBMITTER: Lian JJ 

PROVIDER: S-EPMC7139822 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature