The Human Adult Subtype Ach Receptor Channel Has High Ca2+ Permeability and Predisposes to Endplate Ca2+ Overloading.
From: 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.
The Journal of physiology
- Publish Date: May 2006
- ISSN: 0022-3751
- Volume: 573
- Issue: Pt 1
- Pages: 35-43
- Medium: Print
- Language: English
- Citation (JAMA): Fucile Sergio, Sucapane Antonietta, Grassi Francesca, et al. The Human Adult Subtype Ach Receptor Channel Has High Ca2+ Permeability and Predisposes to Endplate Ca2+ Overloading.. J. Physiol. (Lond.) May 2006;573:35-43
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 nicotinic AChR, with the exception of alpha7-containing AChRs (Pf > 10%); and that neither the alphaG153S nor the alphaV249F 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.
Mesh Headings (Keywords): Adult, Animals, Calcium, Cell Line, Humans, Mice, Motor Endplate, Muscle Fibers, Mutagenesis, Neurotoxins, Patch-Clamp Techniques, Pituitary Gland, Protein Subunits, Rats, Receptors, Nicotinic, Synaptic Transmission, Transfection
Check for Full Text / PubMed Unique Identifier (PMID): 16527851
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