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Mechanism of gating and partial agonist action in the glycine receptor.

Yu J, Zhu H, Lape R, Greiner T, Du J, Lü W, Sivilotti L, Gouaux E
Cell 184 957-968.e21 (2021)
Related entries: 6plo, 6plp, 6plq, 6plr, 6pls, 6plt, 6plu, 6plv, 6plw, 6plx, 6ply, 6plz, 6pm0, 6pm1, 6pm2, 6pm3, 6pm4, 6pm5, 6pxd

Cited: 45 times
EuropePMC logo PMID: 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.

Reviews - 6pm6 mentioned but not cited (2)

  1. Detergent-Free Isolation of Membrane Proteins and Strategies to Study Them in a Near-Native Membrane Environment. Krishnarjuna B, Ramamoorthy A. Biomolecules 12 1076 (2022)
  2. Structure and Mechanism of Glycine Receptor Elucidated by Cryo-Electron Microscopy. Zhu H. Front Pharmacol 13 925116 (2022)

Articles - 6pm6 mentioned but not cited (5)

  1. Mechanism of gating and partial agonist action in the glycine receptor. Yu J, Zhu H, Lape R, Greiner T, Du J, Lü W, Sivilotti L, Gouaux E. Cell 184 957-968.e21 (2021)
  2. The intracellular domain of homomeric glycine receptors modulates agonist efficacy. Ivica J, Lape R, Jazbec V, Yu J, Zhu H, Gouaux E, Gold MG, Sivilotti LG. J Biol Chem 296 100387 (2021)
  3. Architecture and assembly mechanism of native glycine receptors. Zhu H, Gouaux E. Nature 599 513-517 (2021)
  4. Illumination of a progressive allosteric mechanism mediating the glycine receptor activation. Shi S, Lefebvre SN, Peverini L, Cerdan AH, Milán Rodríguez P, Gielen M, Changeux JP, Cecchini M, Corringer PJ. Nat Commun 14 795 (2023)
  5. Lateral fenestrations in the extracellular domain of the glycine receptor contribute to the main chloride permeation pathway. Cerdan AH, Peverini L, Changeux JP, Corringer PJ, Cecchini M. Sci Adv 8 eadc9340 (2022)


Reviews citing this publication (9)

  1. Direct Structural Insights into GABAA Receptor Pharmacology. Kim JJ, Hibbs RE. Trends Biochem Sci 46 502-517 (2021)
  2. Druggable Lipid Binding Sites in Pentameric Ligand-Gated Ion Channels and Transient Receptor Potential Channels. Cheng WWL, Arcario MJ, Petroff JT. Front Physiol 12 798102 (2021)
  3. Benzodiazepine Modulation of GABAA Receptors: A Mechanistic Perspective. Goldschen-Ohm MP. Biomolecules 12 1784 (2022)
  4. Current Developments in Native Nanometric Discoidal Membrane Bilayer Formed by Amphipathic Polymers. Esmaili M, Eldeeb MA, Moosavi-Movahedi AA. Nanomaterials (Basel) 11 (2021)
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  6. Native-like environments afford novel mechanistic insights into membrane proteins. Notti RQ, Walz T. Trends Biochem Sci 47 561-569 (2022)
  7. Positive Allosteric Modulators of Glycine Receptors and Their Potential Use in Pain Therapies. Gallagher CI, Ha DA, Harvey RJ, Vandenberg RJ. Pharmacol Rev 74 933-961 (2022)
  8. Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels. Ananchenko A, Hussein TOK, Mody D, Thompson MJ, Baenziger JE. Biomolecules 12 814 (2022)
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Articles citing this publication (29)

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  5. Probing solution structure of the pentameric ligand-gated ion channel GLIC by small-angle neutron scattering. Lycksell M, Rovšnik U, Bergh C, Johansen NT, Martel A, Porcar L, Arleth L, Howard RJ, Lindahl E. Proc Natl Acad Sci U S A 118 e2108006118 (2021)
  6. Detergent-Free Membrane Protein Purification Using SMA Polymer. Broadbent L, Depping P, Lodé A, Vaitsopoulou A, Hardy D, Ayub H, Mitchell-White J, Kerr ID, Goddard AD, Bill RM, Rothnie AJ. Methods Mol Biol 2507 389-404 (2022)
  7. Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A. Lam AK, Dutzler R. EMBO J 42 e115030 (2023)
  8. Membrane protein extraction and purification using partially-esterified SMA polymers. Hawkins OP, Jahromi CPT, Gulamhussein AA, Nestorow S, Bahra T, Shelton C, Owusu-Mensah QK, Mohiddin N, O'Rourke H, Ajmal M, Byrnes K, Khan M, Nahar NN, Lim A, Harris C, Healy H, Hasan SW, Ahmed A, Evans L, Vaitsopoulou A, Akram A, Williams C, Binding J, Thandi RK, Joby A, Guest A, Tariq MZ, Rasool F, Cavanagh L, Kang S, Asparuhov B, Jestin A, Dafforn TR, Simms J, Bill RM, Goddard AD, Rothnie AJ. Biochim Biophys Acta Biomembr 1863 183758 (2021)
  9. Novel Functional Properties of Missense Mutations in the Glycine Receptor β Subunit in Startle Disease. Piro I, Eckes AL, Kasaragod VB, Sommer C, Harvey RJ, Schaefer N, Villmann C. Front Mol Neurosci 14 745275 (2021)
  10. Aminomethanesulfonic acid illuminates the boundary between full and partial agonists of the pentameric glycine receptor. Ivica J, Zhu H, Lape R, Gouaux E, Sivilotti LG. Elife 11 e79148 (2022)
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  13. Cesium activates the neurotransmitter receptor for glycine. Fricke S, Harnau M, Hetsch F, Liu H, Leonhard J, Eylmann A, Knauff P, Sun H, Semtner M, Meier JC. Front Mol Neurosci 16 1018530 (2023)
  14. Comprehensive behavioral analyses of mice with a glycine receptor alpha 4 deficiency. Darwish M, Hattori S, Nishizono H, Miyakawa T, Yachie N, Takao K. Mol Brain 16 44 (2023)
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  18. Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations. Mhashal AR, Yoluk O, Orellana L. Front Mol Biosci 9 890851 (2022)
  19. Influence of effective polarization on ion and water interactions within a biomimetic nanopore. Phan LX, Lynch CI, Crain J, Sansom MSP, Tucker SJ. Biophys J 121 2014-2026 (2022)
  20. Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel. Dalal V, Arcario MJ, Petroff JT, Tan BK, Dietzen NM, Rau MJ, Fitzpatrick JAJ, Brannigan G, Cheng WWL. Nat Commun 15 25 (2024)
  21. Molecular Investigation of Chicken Acid-Sensing Ion Channel 1 β11-12 Linker Isomerization and Channel Kinetics. Rook ML, Ananchenko A, Musgaard M, MacLean DM. Front Cell Neurosci 15 761813 (2021)
  22. Mutational analysis to explore long-range allosteric couplings involved in a pentameric channel receptor pre-activation and activation. Lefebvre SN, Taly A, Menny A, Medjebeur K, Corringer PJ. Elife 10 e60682 (2021)
  23. Neuroprotection elicited by taurine in sporadic Alzheimer-like disease: benefits on memory and control of neuroinflammation in the hippocampus of rats. Huf F, Gutierres JM, da Silva GN, Zago AM, Koenig LFC, Fernandes MC. Mol Cell Biochem (2023)
  24. Open-channel structure of a pentameric ligand-gated ion channel reveals a mechanism of leaflet-specific phospholipid modulation. Petroff JT, Dietzen NM, Santiago-McRae E, Deng B, Washington MS, Chen LJ, Trent Moreland K, Deng Z, Rau M, Fitzpatrick JAJ, Yuan P, Joseph TT, Hénin J, Brannigan G, Cheng WWL. Nat Commun 13 7017 (2022)
  25. Sterol derivative binding to the orthosteric site causes conformational changes in an invertebrate Cys-loop receptor. De Gieter S, Gallagher CI, Wijckmans E, Pasini D, Ulens C, Efremov RG. Elife 12 e86029 (2023)
  26. Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs. Kumar A, Kindig K, Rao S, Zaki AM, Basak S, Sansom MSP, Biggin PC, Chakrapani S. Nat Commun 13 4862 (2022)
  27. Structural basis for partial agonism in 5-HT3A receptors. Felt K, Stauffer M, Salas-Estrada L, Guzzo PR, Xie D, Huang J, Filizola M, Chakrapani S. Nat Struct Mol Biol (2024)
  28. Structure and function at the lipid-protein interface of a pentameric ligand-gated ion channel. Kumar P, Cymes GD, Grosman C. Proc Natl Acad Sci U S A 118 (2021)
  29. The molecular basis of drug selectivity for α5 subunit-containing GABAA receptors. Kasaragod VB, Malinauskas T, Wahid AA, Lengyel J, Knoflach F, Hardwick SW, Jones CF, Chen WN, Lucas X, El Omari K, Chirgadze DY, Aricescu AR, Cecere G, Hernandez MC, Miller PS. Nat Struct Mol Biol (2023)


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