Direct Structural Insights into GABAA Receptor Pharmacology.

GABA A receptors are pentameric ligand-gated ion channels that mediate most fast neuronal inhibition in the brain. In addition to their important physiological roles, they are noteworthy in their rich pharmacology; prominent drugs used for anxiety, insomnia, and general anesthesia act through positive modulation of GABA A receptors. Direct structural information for how these drugs work was absent until recently. Efforts in structural biology over the past few years have revealed how important drug classes and natural products interact with the GABA A receptor, providing a foundation for studies in dynamics and structure-guided drug design. Here, we review recent developments in GABA A receptor structural pharmacology, focusing on subunit assemblies of the receptor found at synapses. GABA A receptors are ion channels important in brain function and are the target of chemically diverse and clinically important drugs for insomnia, epilepsy, and anesthesia. Recent structures of GABA A receptors have revealed detailed interactions of the neurotransmitter GABA, benzodiazepines, general anesthetics, and antagonists. Intravenous anesthetics bind in both common and distinctive membrane sites. Electrophysiological and molecular dynamics studies build off the static structures, to probe mechanisms of potentiation and inhibition by chemically diverse compounds. [ABSTRACT FROM AUTHOR]