Speaker: Dr Shaotong Zhu, Postdoctoral Fellow - Departments of Neurosciences and Biophysics, University of Texas Southwestern Medical Center

Title: Structural Mechanisms of Fast Inhibitory Neurotransmission

Abstract: Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter γ-aminobutyric acid (GABA) and its synaptic target, the GABAA receptor. Dysfunction of this receptor results in neurological disorders and mental illnesses including epilepsy, anxiety and insomnia. The GABAA receptor is also a prolific target for therapeutic, illicit, and recreational drugs, including benzodiazepines, barbiturates, anesthetics and ethanol. Here we present high resolution cryo-electron microscopy structures of the human α1β2γ2 GABAA receptor, the predominant isoform in the adult brain. The receptor architecture reveals unique heteromeric interactions for this important class of inhibitory neurotransmitter receptors. The structures of the receptor in complex with GABA and the benzodiazepine site modulators reveal principles of ligand selectivity among different classes of subunit interfaces in the heteropentameric assembly. This work provides a template for understanding receptor modulation by GABA and benzodiazepines, and will assist rational approaches to therapeutic targeting of this receptor for neurological disorders and mental illness.