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Structure of a human synaptic GABA-A receptor

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the GABA-A receptor. Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GA...

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Detalles Bibliográficos
Autores principales: Zhu, Shaotong, Noviello, Colleen M., Teng, Jinfeng, Walsh, Richard M., Kim, Jeong Joo, Hibbs, Ryan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220708/
https://www.ncbi.nlm.nih.gov/pubmed/29950725
http://dx.doi.org/10.1038/s41586-018-0255-3
Descripción
Sumario:Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the 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, anesthetics and ethanol. We present high resolution cryo-electron microscopy structures of the human α1β2γ2 GABA-A receptor, the predominant isoform in the adult brain. The receptor is bound to 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 receptors. 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.