Structure of a human synaptic GABA(A) receptor | |
Article | |
关键词: AMINOBUTYRIC ACID(A) RECEPTOR; BENZODIAZEPINE BINDING-SITE; GAMMA-SUBUNIT; BETA-SUBUNIT; A RECEPTORS; AGONIST; MODULATION; PHARMACOLOGY; INSIGHTS; AFFINITY; | |
DOI : 10.1038/s41586-018-0255-3 | |
来源: SCIE |
【 摘 要 】
Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (gamma-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABA(A) receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABA(A) receptor is also a prolific target for therapeutic, illicit and recreational drugs, including benzodiazepines, barbiturates, anaesthetics and ethanol. Here we present high-resolution cryo-electron microscopy structures of the human alpha 1 beta 2 gamma 2 GABA(A) receptor, the predominant isoform in the adult brain, in complex with GABA and the benzodiazepine site antagonist flumazenil, the first-line clinical treatment for benzodiazepine overdose. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptor. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.
【 授权许可】
Free