Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities

gamma-Aminobutyric acid type A (GABA(A)) receptors are pentameric ligand-gated ion channels abundant in the central nervous system and are prolific drug targets for treating anxiety, sleep disorders and epilepsy. Diverse small molecules exert a spectrum of effects on gamma-aminobutyric acid type A (GABA(A)) receptors by acting at the classical benzodiazepine site. They can potentiate the response to GABA, attenuate channel activity, or counteract modulation by other ligands. Structural mechanisms underlying the actions of these drugs are not fully understood. Here we present two high-resolution structures of GABA(A) receptors in complex with zolpidem, a positive allosteric modulator and heavily prescribed hypnotic, and DMCM, a negative allosteric modulator with convulsant and anxiogenic properties. These two drugs share the extracellular benzodiazepine site at the alpha/gamma subunit interface and two transmembrane sites at beta/alpha interfaces. Structural analyses reveal a basis for the subtype selectivity of zolpidem that underlies its clinical success. Molecular dynamics simulations provide insight into how DMCM switches from a negative to a positive modulator as a function of binding site occupancy. Together, these findings expand our understanding of how GABA(A) receptor allosteric modulators acting through a common site can have diverging activities. GABA(A) receptors are important targets for anxiety, sedation and anesthesia. Here, the authors present structures bound by zolpidem (Ambien), the most prescribed hypnotic in the US, and DMCM, a negative modulator, providing insights into receptor modulation.

Automated summary

GABA(A) receptors are important drug targets in the central nervous system for treating anxiety, sleep disorders, and epilepsy. This study presents two high-resolution structures of GABA(A) receptors bound by the drugs zolpidem and DMCM, providing insights into receptor modulation.