Gamma-aminobutyric acid receptor subunit alpha-1
GABA-A receptor complex
Structural basis of neurosteroid anesthetic action on GABA<sub>A</sub> receptors.
Type A γ-aminobutyric acid receptors (GABA<sub>A</sub>Rs) are inhibitory pentameric ligand-gated ion channels in the brain. Many anesthetics and neurosteroids act through binding to the GABA<sub>A</sub>R transmembrane domain (TMD), but the structural basis of their actions is not well understood and no resting-state GABA<sub>A</sub>R structure has been determined. Here, we report crystal structures of apo and the neurosteroid anesthetic alphaxalone-bound desensitized chimeric α1GABA<sub>A</sub>R (ELIC-α1GABA<sub>A</sub>R). The chimera retains the functional and pharmacological properties of GABA<sub>A</sub>Rs, including potentiation, activation and desensitization by alphaxalone. The apo-state structure reveals an unconventional activation gate at the intracellular end of the pore. The desensitized structure illustrates molecular determinants for alphaxalone binding to an inter-subunit TMD site. These structures suggest a plausible signaling pathway from alphaxalone binding at the bottom of the TMD to the channel gate in the pore-lining TM2 through the TM1-TM2 linker. The study provides a framework to discover new GABA<sub>A</sub>R modulators with therapeutic potential.