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This Article Full Text Full Text (PDF) All Versions of this Article: 573/1/35    most recent jphysiol.2006.108092v2 jphysiol.2006.108092v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fucile, S. Articles by Engel, A. G. Search for Related Content PubMed PubMed Citation Articles by Fucile, S. Articles by Engel, A. G. Related Collections Cellular

¹ Pasteur Institute -Cenci Bolognetti Foundation & Department of Human Physiology and Pharmacology & Centre of Excellence for Biology and Molecular Medicine, University of Rome "La Sapienza", Piazzale Aldo Moro 5; I-00185 Rome, Italy
² Institute San Raffaele - TOSINVEST SANITA', Via della Pisana 235; I-00139 Roma, Italy
³ Muscle Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA

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 (P_f), for AChRs harbouring the G153S or the V249F slow-channel mutation, and for wild-type human AChRs in which P_f 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 P_f of the wild-type human endplate AChR was unexpectedly high (P_f 7%), but neither the V249F nor the G153S mutation altered P_f. Fetal human AChRs containing either the wild-type or the mutated subunit had a much lower P_f (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 7-containing AChRs (P_f > 10%); and that neither the G153S nor the V249F mutations affect the P_f 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.

(Received 21 February 2005; accepted after revision 7 March 2006; first published online 9 March 2006)
Corresponding author F. Grassi: Department of Human Physiology and Pharmacology, University of Rome "La Sapienza", Piazzale Aldo Moro 5; I-00185 Rome, Italy. Email: francesca.grassi{at}uniroma1.it

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