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

Creators: Spurny, Radovan; Ramerstorfer, Joachim; Price, Kerry; Brams, Marijke; Ernst, Margot; Nury, Hugues; Verheij, Mark; Legrand, Pierre; Bertrand, Daniel; Bertrand, Sonia; Dougherty, Dennis A.; de Esch, Iwan J. P.; Corringer, Pierre-Jean; Sieghart, Werner; Lummis, Sarah C. R.; Ulens, Chris

Abstract

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.

Additional Information

© 2012 National Academy of Sciences. Freely available online through the PNAS open access option. Edited by Jean-Pierre Changeux, Institut Pasteur, Paris Cedex 15, France, and approved September 10, 2012 (received for review May 24, 2012). Published online before print October 3, 2012. We thank Jessy Winters for assisting with protein preparations, Estelle Neveu for technical assistance with oocyte recordings, and Jan Tytgat for mass spectrometry. For model refinement we used the infrastructure of the Flemish Supercomputer Center funded by the Hercules Foundation and the Flemish Government. This project was supported by Grant KULeuven OT/08/048 (to C.U.); by the European Union Seventh Framework Programme under Grant Agreement HEALTH-F2-2007-202088 (Structure, function and disease of Cys-loop receptors, "NeuroCypres" project) (to W.S., I.J.P.d.E., S.C.R.L., D.B., P.-J.C., and C.U.); by the Wellcome Trust (S.C.R.L. and K.P.); by Austrian Science Fund Grant P19653 (to M.E.); and by National Institutes of Health Grant NS 34407 (to D.A.D.). S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. Author contributions: W.S., S.C.R.L., and C.U. designed research; R.S., J.R., K.P., M.B., M.V., P.L., D.B., S.B., S.C.R.L., and C.U. performed research; M.V., S.B., D.A.D., P.-J.C., S.C.R.L., and C.U. contributed new reagents/analytic tools; R.S., J.R., K.P., M.B., M.E., H.N., M.V., P.L., D.B., S.B., D.A.D., I.J.P.d.E., W.S., S.C.R.L., and C.U. analyzed data; and R.S., J.R., K.P., M.E., M.V., D.B., I.J.P.d.E., P.-J.C., W.S., S.C.R.L., and C.U. wrote the paper.

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Published - PNAS-2012-Spurny-E3028-34.pdf

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