Structural highlights
Disease
GBRG2_HUMAN Childhood absence epilepsy;Dravet syndrome;Generalized epilepsy with febrile seizures-plus. Disease susceptibility is associated with variations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
GBRG2_HUMAN Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responses to histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand-gated chloride channel.[1]
Publication Abstract from PubMed
Most general anaesthetics and classical benzodiazepine drugs act through positive modulation of gamma-aminobutyric acid type A (GABAA) receptors to dampen neuronal activity in the brain(1-5). However, direct structural information on the mechanisms of general anaesthetics at their physiological receptor sites is lacking. Here we present cryo-electron microscopy structures of GABAA receptors bound to intravenous anaesthetics, benzodiazepines and inhibitory modulators. These structures were solved in a lipidic environment and are complemented by electrophysiology and molecular dynamics simulations. Structures of GABAA receptors in complex with the anaesthetics phenobarbital, etomidate and propofol reveal both distinct and common transmembrane binding sites, which are shared in part by the benzodiazepine drug diazepam. Structures in which GABAA receptors are bound by benzodiazepine-site ligands identify an additional membrane binding site for diazepam and suggest an allosteric mechanism for anaesthetic reversal by flumazenil. This study provides a foundation for understanding how pharmacologically diverse and clinically essential drugs act through overlapping and distinct mechanisms to potentiate inhibitory signalling in the brain.
Shared structural mechanisms of general anaesthetics and benzodiazepines.,Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE Nature. 2020 Sep;585(7824):303-308. doi: 10.1038/s41586-020-2654-5. Epub 2020 Sep, 2. PMID:32879488[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR, Seeburg PH. Importance of a novel GABAA receptor subunit for benzodiazepine pharmacology. Nature. 1989 Apr 13;338(6216):582-5. PMID:2538761 doi:http://dx.doi.org/10.1038/338582a0
- ↑ Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM Jr, Lindahl E, Hibbs RE. Shared structural mechanisms of general anaesthetics and benzodiazepines. Nature. 2020 Sep;585(7824):303-308. PMID:32879488 doi:10.1038/s41586-020-2654-5
