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Mechanism of gating and partial agonist action in the glycine receptor.
Yu, Jie; Zhu, Hongtao; Lape, Remigijus; Greiner, Timo; Du, Juan; Lü, Wei; Sivilotti, Lucia; Gouaux, Eric.
  • Yu J; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • Zhu H; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • Lape R; Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.
  • Greiner T; Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK.
  • Du J; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • Lü W; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA.
  • Sivilotti L; Department of Neuroscience, Physiology and Pharmacology, University College London, Medical Sciences Building, Gower Street, London WC1E 6BT, UK. Electronic address: l.sivilotti@ucl.ac.uk.
  • Gouaux E; Vollum Institute, Oregon Health & Science University, Portland, OR 97239, USA; Howard Hughes Medical Institute, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: gouauxe@ohsu.edu.
Cell ; 184(4): 957-968.e21, 2021 02 18.
Article en En | MEDLINE | ID: mdl-33567265
ABSTRACT
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Activación del Canal Iónico / Receptores de Glicina Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Activación del Canal Iónico / Receptores de Glicina Límite: Animals / Humans Idioma: En Año: 2021 Tipo del documento: Article