A structural perspective on GABAA receptor pharmacology

GABA_A receptors are pentameric ligand-gated chloride channels of crucial importance for the vertebrate nervous system physiology. They typically modulate the fast inhibitory neurotransmission, and represent the target receptors for major classes of drugs used in the clinic, such as benzodiazepines and general anesthetics. Recent technological progress in structural biology, in particular single-particle cryo-electron microscopy, has led to fundamental advances in understanding the detailed organization and signalling mechanisms of major GABA_A receptor subtypes. This effort culminated with the high-resolution structural analysis of an intact, full-length human heteropentameric receptor, α1β3γ2, in a lipid bilayer and in complex with small molecule ligands including the commonly used benzodiazepines diazepam (Valium) and alprazolam (Xanax). These structures reveal multiple aspects of receptor activation and provide a path for rational design of subunit-specific GABA_A receptor modulators.