| First Author | Laverty D | Year | 2019 |
| Journal | Nature | Volume | 565 |
| Issue | 7740 | Pages | 516-520 |
| PubMed ID | 30602789 | Mgi Jnum | J:320133 |
| Mgi Id | MGI:6869972 | Doi | 10.1038/s41586-018-0833-4 |
| Citation | Laverty D, et al. (2019) Cryo-EM structure of the human alpha1beta3gamma2 GABAA receptor in a lipid bilayer. Nature 565(7740):516-520 |
| abstractText | Type A gamma-aminobutyric acid (GABAA) receptors are pentameric ligand-gated ion channels and the main drivers of fast inhibitory neurotransmission in the vertebrate nervous system(1,2). Their dysfunction is implicated in a range of neurological disorders, including depression, epilepsy and schizophrenia(3,4). Among the numerous assemblies that are theoretically possible, the most prevalent in the brain are the alpha1beta2/3gamma2 GABAA receptors(5). The beta3 subunit has an important role in maintaining inhibitory tone, and the expression of this subunit alone is sufficient to rescue inhibitory synaptic transmission in beta1-beta3 triple knockout neurons(6). So far, efforts to generate accurate structural models for heteromeric GABAA receptors have been hampered by the use of engineered receptors and the presence of detergents(7-9). Notably, some recent cryo-electron microscopy reconstructions have reported 'collapsed' conformations(8,9); however, these disagree with the structure of the prototypical pentameric ligand-gated ion channel the Torpedo nicotinic acetylcholine receptor(10,11), the large body of structural work on homologous homopentameric receptor variants(12) and the logic of an ion-channel architecture. Here we present a high-resolution cryo-electron microscopy structure of the full-length human alpha1beta3gamma2L-a major synaptic GABAA receptor isoform-that is functionally reconstituted in lipid nanodiscs. The receptor is bound to a positive allosteric modulator 'megabody' and is in a desensitized conformation. Each GABAA receptor pentamer contains two phosphatidylinositol-4,5-bisphosphate molecules, the head groups of which occupy positively charged pockets in the intracellular juxtamembrane regions of alpha1 subunits. Beyond this level, the intracellular M3-M4 loops are largely disordered, possibly because interacting post-synaptic proteins are not present. This structure illustrates the molecular principles of heteromeric GABAA receptor organization and provides a reference framework for future mechanistic investigations of GABAergic signalling and pharmacology. |
