Drug discovery: GABA-A structure uncovers how benzodiazepines work

The structure of the type-A gamma-aminobutyric acid (GABA-A) receptor - which mediates the actions of a broad range of medicinal and recreational drugs and is also the target of treatments for neurological disorders and mental illnesses - is reported online in Nature this week. These findings could assist the future development of drug therapies for these conditions.

Fast inhibitory neurotransmission in the brain is principally mediated by the neurotransmitter GABA and its synaptic target, the GABA-A receptor. GABA-A receptors have a major role in psychological activity in the central nervous system; dysfunction of this receptor can lead to disorders such as epilepsy, anxiety and insomnia. The GABA-A receptor is also a target for drugs, including barbiturates, anaesthetics, alcohol, and the benzodiazepines diazepam (Valium) and alprazolam (Xanax).

Ryan Hibbs and colleagues report structures, determined by cryo-electron microscopy, of the GABA-A receptor bound to GABA and flumazenil, an overdose antidote. The authors show how the receptor is affected by benzodiazepines. They also reveal sites at specific interfaces between the protein subunits of the receptor, which represent potential targets for drug development. Their work could further our understanding of Cys-loop receptor family members and aid development of drugs targeting the GABA-A receptor.