The dual-gate model for pentameric ligand-gated ion channels activation and desensitization

The Journal of Physiology
Marc Gielen, Pierre-Jean Corringer

Abstract

Pentameric ligand-gated ion channels (pLGICs) mediate fast neurotransmission in the nervous system. Their dysfunction is associated with psychiatric, neurological and neurodegenerative disorders such as schizophrenia, epilepsy and Alzheimer's disease. Understanding their biophysical and pharmacological properties, at both the functional and the structural level, thus holds many therapeutic promises. In addition to their agonist-elicited activation, most pLGICs display another key allosteric property, namely desensitization, in which they enter a shut state refractory to activation upon sustained agonist binding. While the activation mechanisms of several pLGICs have been revealed at near-atomic resolution, the structural foundation of desensitization has long remained elusive. Recent structural and functional data now suggest that the activation and desensitization gates are distinct, and are located at both sides of the ion channel. Such a 'dual gate mechanism' accounts for the marked allosteric effects of channel blockers, a feature illustrated herein by theoretical kinetics simulations. Comparison with other classes of ligand- and voltage-gated ion channels shows that this dual gate mechanism emerges as a common theme for th...Continue Reading

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Citations

Oct 9, 2019·Nature Chemical Biology·Camille M HénaultChris Ulens
Dec 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Nicholas B GurosJeffery B Klauda
Dec 14, 2018·Proceedings of the National Academy of Sciences of the United States of America·Haidai HuMarc Delarue
Jan 4, 2019·Nature·Simonas MasiulisA Radu Aricescu
Mar 29, 2020·Frontiers in Pharmacology·César O LaraGonzalo E Yévenes
Jun 8, 2018·The Journal of Physiology·Derek Bowie
Jun 6, 2018·Frontiers in Molecular Neuroscience·Ulrike BreitingerHans-Georg Breitinger
Oct 25, 2020·Nature Communications·Marc GielenPierre-Jean Corringer
Jan 14, 2021·The Journal of Physical Chemistry. B·Shanlin RaoMark S P Sansom
Dec 5, 2020·Brain Sciences·Matthew B PhillipsJon W Johnson
Jan 29, 2021·British Journal of Pharmacology·Teresa Minguez-ViñasAna Sofia Oliveira
Apr 10, 2020·Neuropharmacology·Anant GharpureRyan E Hibbs
Apr 21, 2020·Biochimica Et Biophysica Acta. Biomembranes·Mackenzie J Thompson, John E Baenziger
Mar 7, 2021·Trends in Biochemical Sciences·Jeong Joo Kim, Ryan E Hibbs
May 24, 2020·Current Opinion in Structural Biology·Zoe Cournia, Alexios Chatzigoulas
Jun 2, 2021·The Journal of General Physiology·Matthew L RookDavid M MacLean
May 22, 2021·Current Opinion in Pharmacology·Frédéric Knoflach, Daniel Bertrand
Sep 25, 2021·Biochemical Pharmacology·Nawid MadjrohAnders A Jensen
Sep 19, 2020·Biophysical Journal·Noelia Rodriguez AraujoJeremías Corradi

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