5nkj Citations

Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels.

Cell Rep 23 993-1004 (2018)
Related entries: 5muo, 5mur, 5mvn, 5mzq, 6emx

Cited: 18 times
EuropePMC logo PMID: 29694907

Abstract

Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

Articles - 5nkj mentioned but not cited (1)

  1. Electrostatics, proton sensor, and networks governing the gating transition in GLIC, a proton-gated pentameric ion channel. Hu H, Ataka K, Menny A, Fourati Z, Sauguet L, Corringer PJ, Koehl P, Heberle J, Delarue M. Proc Natl Acad Sci U S A 115 E12172-E12181 (2018)


Reviews citing this publication (4)

  1. Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery. Hemmings HC, Riegelhaupt PM, Kelz MB, Solt K, Eckenhoff RG, Orser BA, Goldstein PA. Trends Pharmacol Sci 40 464-481 (2019)
  2. Understanding the Effects of Anesthesia on Cortical Electrophysiological Recordings: A Scoping Review. Sorrenti V, Cecchetto C, Maschietto M, Fortinguerra S, Buriani A, Vassanelli S. Int J Mol Sci 22 1286 (2021)
  3. 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)
  4. 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)

Articles citing this publication (13)

  1. Shared structural mechanisms of general anaesthetics and benzodiazepines. Kim JJ, Gharpure A, Teng J, Zhuang Y, Howard RJ, Zhu S, Noviello CM, Walsh RM, Lindahl E, Hibbs RE. Nature 585 303-308 (2020)
  2. Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity. Heusser SA, Lycksell M, Wang X, McComas SE, Howard RJ, Lindahl E. Proc Natl Acad Sci U S A 115 10672-10677 (2018)
  3. Dynamic closed states of a ligand-gated ion channel captured by cryo-EM and simulations. Rovšnik U, Zhuang Y, Forsberg BO, Carroni M, Yvonnesdotter L, Howard RJ, Lindahl E. Life Sci Alliance 4 e202101011 (2021)
  4. Mechanistic insights into volatile anesthetic modulation of K2P channels. Wague A, Joseph TT, Woll KA, Bu W, Vaidya KA, Bhanu NV, Garcia BA, Nimigean CM, Eckenhoff RG, Riegelhaupt PM. Elife 9 e59839 (2020)
  5. Structural basis for allosteric transitions of a multidomain pentameric ligand-gated ion channel. Hu H, Howard RJ, Bastolla U, Lindahl E, Delarue M. Proc Natl Acad Sci U S A 117 13437-13446 (2020)
  6. Markov state models of proton- and pore-dependent activation in a pentameric ligand-gated ion channel. Bergh C, Heusser SA, Howard R, Lindahl E. Elife 10 e68369 (2021)
  7. 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)
  8. The Glycine Receptor Allosteric Ligands Library (GRALL). Cerdan AH, Sisquellas M, Pereira G, Barreto Gomes DE, Changeux JP, Cecchini M. Bioinformatics 36 3379-3384 (2020)
  9. Menthol Binding to the Human α4β2 Nicotinic Acetylcholine Receptor Facilitated by Its Strong Partitioning in the Membrane. Shahoei R, Tajkhorshid E. J Phys Chem B 124 1866-1880 (2020)
  10. 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)
  11. Structural evidence for the binding of monocarboxylates and dicarboxylates at pharmacologically relevant extracellular sites of a pentameric ligand-gated ion channel. Fourati Z, Sauguet L, Delarue M. Acta Crystallogr D Struct Biol 76 668-675 (2020)
  12. 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)
  13. Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment. Bharambe N, Li Z, Seiferth D, Balakrishna AM, Biggin PC, Basak S. Nat Commun 15 2967 (2024)