(+)-Catharanthine potentiates the GABA_A receptor by binding to a transmembrane site at the β(+)/α(-) interface near the TM2-TM3 loop.

ABSTRACT: (+)-Catharanthine, a coronaridine congener, potentiates the γ-aminobutyric acid type A receptor (GABA_AR) and induces sedation through a non-benzodiazepine mechanism, but the specific site of action and intrinsic mechanism have not beendefined. Here, we describe GABA_AR subtype selectivity and location of the putative binding site for (+)-catharanthine using electrophysiological, site-directed mutagenesis, functional competition, and molecular docking experiments. Electrophysiological and in silico experiments showed that (+)-catharanthine potentiates the responses to low, subsaturating GABA at β2/3-containing GABA_ARs 2.4-3.5 times more efficaciously than at β1-containing GABA_ARs. The activity of (+)-catharanthine is reduced by the β2(N265S) mutati

SUBMITTER: Arias HR 

PROVIDER: S-EPMC9178925 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature