8g4o | pdb_00008g4o
Native GABA-A receptor from the mouse brain, alpha1-beta2-gamma2 subtype, in complex with didesethylflurazepam and endogenous GABA
Structural highlights
FunctionGBRA1_MOUSE Alpha subunit of the heteropentameric ligand-gated chloride channel gated by Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain. GABA-gated chloride channels, also named GABA(A) receptors (GABAAR), consist of five subunits arranged around a central pore and contain GABA active binding site(s) located at the alpha and beta subunit interface(s) (PubMed:27129275). When activated by GABA, GABAARs selectively allow the flow of chloride anions across the cell membrane down their electrochemical gradient (By similarity). Alpha-1/GABRA1-containing GABAARs are largely synaptic (By similarity). Chloride influx into the postsynaptic neuron following GABAAR opening decreases the neuron ability to generate a new action potential, thereby reducing nerve transmission (By similarity). GABAARs containing alpha-1 and beta-2 or -3 subunits exhibit synaptogenic activity; the gamma-2 subunit being necessary but not sufficient to induce rapid synaptic contacts formation (PubMed:27129275). GABAARs function also as histamine receptor where histamine binds at the interface of two neighboring beta subunits and potentiates GABA response (By similarity). GABAARs containing alpha, beta and epsilon subunits also permit spontaneous chloride channel activity while preserving the structural information required for GABA-gated openings (By similarity). Alpha-1-mediated plasticity in the orbitofrontal cortex regulates context-dependent action selection (PubMed:25348603). Together with rho subunits, may also control neuronal and glial GABAergic transmission in the cerebellum (PubMed:16945976, PubMed:25422464).[UniProtKB:P08219][UniProtKB:P62813][1] [2] [3] [4] Publication Abstract from PubMedType A gamma-aminobutyric acid receptors (GABA(A)Rs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anaesthetics, sedatives, hypnotics and antidepressants(1-3). However, our understanding of GABA(A)R pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from 19 different subunits(4) and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABA(A)R assemblies containing the widely expressed alpha1 subunit and elucidate their structures in complex with drugs used to treat insomnia (zolpidem (ZOL) and flurazepam) and postpartum depression (the neurosteroid allopregnanolone (APG)). Using cryo-electron microscopy (cryo-EM) analysis and single-molecule photobleaching experiments, we uncover three major structural populations in the brain: the canonical alpha1beta2gamma2 receptor containing two alpha1 subunits, and two assemblies containing one alpha1 and either an alpha2 or alpha3 subunit, in which the single alpha1-containing receptors feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, APG is bound at the transmembrane alpha/beta subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABA(A)Rs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify the ion channel pore and the binding sites for GABA and insomnia medications. Our data reveal the major alpha1-containing GABA(A)R assemblies, bound with endogenous neurosteroid, thus defining a structural landscape from which subtype-specific drugs can be developed. Cryo-EM structures reveal native GABA(A) receptor assemblies and pharmacology.,Sun C, Zhu H, Clark S, Gouaux E Nature. 2023 Oct;622(7981):195-201. doi: 10.1038/s41586-023-06556-w. Epub 2023 , Sep 20. PMID:37730991[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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