The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ overloading

The Journal of Physiology
S FucileA G Engel

Abstract

Slow-channel congenital myasthenic syndrome, caused by mutations in subunits of the endplate ACh receptor (AChR), results in prolonged synaptic currents and excitotoxic injury of the postsynaptic region by Ca2+ overloading. The Ca2+ overloading could be due entirely to the prolonged openings of the AChR channel or could be abetted by enhanced Ca2+ permeability of the mutant channels. We therefore measured the fractional Ca2+ current, defined as the percentage of the total ACh-evoked current carried by Ca2+ ions (Pf), for AChRs harbouring the alphaG153S or the alphaV249F slow-channel mutation, and for wild-type human AChRs in which Pf has not yet been determined. Experiments were performed in transiently transfected GH4C1 cells and human myotubes with simultaneous recording of ACh-evoked whole-cell currents and fura-2 fluorescence signals. We found that the Pf of the wild-type human endplate AChR was unexpectedly high (Pf approximately 7%), but neither the alphaV249F nor the alphaG153S mutation altered Pf. Fetal human AChRs containing either the wild-type or the mutated alpha subunit had a much lower Pf (2-3%). We conclude that the Ca2+ permeability of human endplate AChRs is higher than that reported for any other human nicotin...Continue Reading

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Citations

Jan 12, 2013·Pflügers Archiv : European journal of physiology·Jerrel L Yakel
Aug 19, 2009·Journal of Molecular Neuroscience : MN·Andrew G EngelSteven M Sine
Feb 22, 2012·Journal of Molecular Neuroscience : MN·Jian-xin Shen, Jerrel L Yakel
Jan 26, 2011·Proceedings of the National Academy of Sciences of the United States of America·Atsuo NishinoYasushi Okamura
Dec 1, 2011·Proceedings of the National Academy of Sciences of the United States of America·Eleonora PalmaRicardo Miledi
Sep 2, 2009·The Journal of General Physiology·Sergio Fucile, Francesca Grassi
Oct 28, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Haipeng ZhuChristopher M Gomez
Nov 26, 2010·Pflügers Archiv : European journal of physiology·Claudia MoriconiFrancesca Grassi
Nov 2, 2013·Pflügers Archiv : European journal of physiology·José O Colón-Sáez, Jerrel L Yakel
Sep 7, 2014·Molecular Biology and Evolution·Marcela LipovsekAna Belén Elgoyhen
Jul 16, 2008·Annals of Neurology·Duygu SelcenAndrew G Engel
Jun 11, 2010·Journal of Neurochemistry·Claudia MoriconiFrancesca Grassi
Mar 21, 2012·The Journal of Physiology·Cristina DeflorioFrancesca Grassi
Oct 27, 2017·Annals of the New York Academy of Sciences·Jaap J PlompJan J G M Verschuuren
Apr 3, 2016·The European Journal of Neuroscience·Elizabeth M van der PijlJaap J Plomp
Oct 6, 2020·Frontiers in Molecular Neuroscience·Hakan CetinRichard Webster
May 15, 2021·Clinical Toxicology : the Official Journal of the American Academy of Clinical Toxicology and European Association of Poisons Centres and Clinical Toxicologists·Kosala N DissanayakeRichard R Ribchester
Nov 9, 2021·The Journal of Physiology·Kosala N DissanayakeRichard R Ribchester

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