Cryo-electron microscopy structures of native type A GABA receptors from human brain reveal diverse subunit compositions, protein binding partners and binding sites for antiepileptic drugs.

A new study has uncovered a critical molecular mechanism behind alcohol's effects on the brain. Researchers found that a previously uncharacterized protein, TMEM132B, amplifies alcohol's influence on GABAA receptors.

Type A GABA (γ-aminobutyric acid) receptors (GABAA receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics1,2. These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABAA receptors in the human brain have been inferred from subunit localization in tissue1,3, functional measurements and structural analysis from recombinant expression4–7 and in mice8. However, the arrangements of subunits that co-assemble physiologically in native human GABAA receptors remain unknown. Here we isolated α1 subunit-containing GABAA receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefin

Cryo-electron microscopy structures of native type A GABA receptors from human brain reveal diverse subunit compositions, protein binding partners and binding sites for antiepileptic drugs.

Paradoxically, mutations that enhance GABAA receptor function cause severe epilepsy. Using a mouse model of a human gain-of-function GABAA receptor mutatio

Cryo-electron microscopy structures of native type A GABA receptors from human brain reveal diverse subunit compositions, protein binding partners and binding sites for antiepileptic drugs.

Cryo-electron microscopy structures of native type A GABA receptors from human brain reveal diverse subunit compositions, protein binding partners and binding sites for antiepileptic drugs.

Type-A γ-aminobutyric receptors (GABAARs) are fast pentameric ligand gated ion channels (pLGICs)[1][1]–[5][2]. Within a millisecond, saturating agonist concentrations trigger activity bursts consistin...

Cryo-electron microscopy structures of native type A GABA receptors from human brain reveal diverse subunit compositions, protein binding partners and binding sites for antiepileptic drugs.

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