Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines

Radovan Spurny (1) , Joachim Ramerstorfer (2) , Kerry Price (3) , Marijke Brams (1) , Margot Ernst (2) , Hugues Nury (4) , Mark Verheij (5) , Pierre Legrand (6) , Daniel Bertrand , Sonia Bertrand , Dennis Dougherty (7) , Iwan de Esch (5) , Pierre-Jean Corringer (4) , Werner Sieghart (2) , Sarah Lummis (3) , Chris Ulens (1)

1 KU Leuven - Catholic University of Leuven - Katholieke Universiteit Leuven
2 Medizinische Universität Wien = Medical University of Vienna
3 CAM - University of Cambridge [UK]
4 Récepteurs-Canaux
5 VU - Vrije Universiteit Amsterdam [Amsterdam]
6 SSOLEIL - Synchrotron SOLEIL
7 CALTECH - California Institute of Technology

GABA(A) receptors are pentameric ligand-gated ion channels involved in fast inhibitory neurotransmission and are allosterically modulated by the anxiolytic, anticonvulsant, and sedative-hypnotic benzodiazepines. Here we show that the prokaryotic homolog ELIC also is activated by GABA and is modulated by benzodiazepines with effects comparable to those at GABA(A) receptors. Crystal structures reveal important features of GABA recognition and indicate that benzodiazepines, depending on their concentration, occupy two possible sites in ELIC. An intrasubunit site is adjacent to the GABA-recognition site but faces the channel vestibule. A second intersubunit site partially overlaps with the GABA site and likely corresponds to a low-affinity benzodiazepine-binding site in GABA(A) receptors that mediates inhibitory effects of the benzodiazepine flurazepam. Our study offers a structural view how GABA and benzodiazepines are recognized at a GABA-activated ion channel.

Domains: Life Sciences [q-bio]; Pharmaceutical sciences; Pharmacology; Life Sciences [q-bio]; Neurons and Cognition [q-bio.NC]

Radovan Spurny, Joachim Ramerstorfer, Kerry Price, Marijke Brams, Margot Ernst, et al.. Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 (44), pp.E3028 - E3034. ⟨10.1073/pnas.1208208109⟩. ⟨pasteur-01721946⟩