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

Fourati Z, Howard RJ, Heusser SA, Hu H, Ruza RR, Sauguet L, Lindahl E, Delarue M
Cell Rep 23 993-1004 (2018)
Related entries: 5mur, 5mvn, 5mzq, 5nkj, 6emx

Cited: 20 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 - 5muo mentioned but not cited (2)

  1. 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)
  2. Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels. Koniuszewski F, Vogel FD, Bampali K, Fabjan J, Seidel T, Scholze P, Schmiedhofer PB, Langer T, Ernst M. Front Mol Biosci 9 860246 (2022)


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 (14)



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