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

Sergio Fucile, Antonietta Sucapane, Francesca Grassi, Fabrizio Eusebi, Andrew G. Engel

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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 αG153S or the αV249F slow-channel mutation, and for wild-type human AChRs in which Pf has not yet been determined. Experiments were performed in transiently t]ransfected 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 ∼7%), but neither the αV249F nor the αG153S mutation altered Pf. Fetal human AChRs containing either the wild-type or the mutated α 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 nicotinic AChR, with the exception of α7-containing AChRs (Pf > 10%); and that neither the αG153S nor the αV249F mutations affect the Pf of fetal or adult endplate AChRs. However, the intrinsically high Ca2+ permeability of human AChRs probably predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics.

Original languageEnglish
Pages (from-to)35-43
Number of pages9
JournalJournal of Physiology
Volume573
Issue number1
DOIs
Publication statusPublished - May 15 2006

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Cholinergic Receptors
Permeability
Mutation
Congenital Myasthenic Syndromes
Fura-2
Skeletal Muscle Fibers
Nicotinic Receptors
Muscular Diseases
Fluorescence
Ions
Wounds and Injuries

ASJC Scopus subject areas

  • Physiology

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The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ . / Fucile, Sergio; Sucapane, Antonietta; Grassi, Francesca; Eusebi, Fabrizio; Engel, Andrew G.

In: Journal of Physiology, Vol. 573, No. 1, 15.05.2006, p. 35-43.

Research output: Contribution to journalArticle

Fucile, Sergio ; Sucapane, Antonietta ; Grassi, Francesca ; Eusebi, Fabrizio ; Engel, Andrew G. / The human adult subtype ACh receptor channel has high Ca2+ permeability and predisposes to endplate Ca2+ In: Journal of Physiology. 2006 ; Vol. 573, No. 1. pp. 35-43.
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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 αG153S or the αV249F slow-channel mutation, and for wild-type human AChRs in which Pf has not yet been determined. Experiments were performed in transiently t]ransfected 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 ∼7{\%}), but neither the αV249F nor the αG153S mutation altered Pf. Fetal human AChRs containing either the wild-type or the mutated α 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 nicotinic AChR, with the exception of α7-containing AChRs (Pf > 10{\%}); and that neither the αG153S nor the αV249F mutations affect the Pf of fetal or adult endplate AChRs. However, the intrinsically high Ca2+ permeability of human AChRs probably predisposes to development of the endplate myopathy when opening events of the AChR channel are prolonged by altered AChR-channel kinetics.",
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