TY - JOUR
T1 - Structure of a human synaptic GABAA receptor
AU - Zhu, Shaotong
AU - Noviello, Colleen M.
AU - Teng, Jinfeng
AU - Walsh, Richard M.
AU - Kim, Jeong Joo
AU - Hibbs, Ryan E
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018
Y1 - 2018
N2 - Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA 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 α1β2γ2 GABAA 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.
AB - Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA (γ-aminobutyric acid) and its synaptic target, the type A GABA receptor (GABAA receptor). Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA 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 α1β2γ2 GABAA 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.
UR - http://www.scopus.com/inward/record.url?scp=85049604256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85049604256&partnerID=8YFLogxK
U2 - 10.1038/s41586-018-0255-3
DO - 10.1038/s41586-018-0255-3
M3 - Article
C2 - 29950725
AN - SCOPUS:85049604256
SN - 0028-0836
VL - 559
SP - 67
EP - 88
JO - Nature
JF - Nature
IS - 7712
ER -