Modulation of the Ca2+ permeability of human endplate acetylcholine receptor-channel

Vanessa Piccari, Cristina Deflorio, Rachele Bigi, Francesca Grassi, Sergio Fucile

Research output: Contribution to journalArticlepeer-review

Abstract

In slow-channel congenital myasthenic syndrome, point mutations of the endplate acetylcholine receptor (AChR) prolong channel openings, leading to excessive Ca2+ entry with ensuing endplate degeneration and myasthenic symptoms. The Ca2+ permeability of the human endplate AChR-channel is quite high, and is further increased by two slow-channel mutations in its e{open} subunit, worsening the pathological cascade. To gain further support to the hypothesis that the e{open} subunit plays a crucial role in controlling Ca2+ permeability of endplate AChR-channel, in this work we measured the fractional Ca2+ current (Pf, i.e., the percentage of the total current carried by Ca2+ ions) of a panel of AChR carrying slow-channel mutations in the α, β and e{open} subunits detected in patients (αN217K, αS226Y, αC418W, βV266A, βV266M, e{open}I257F, e{open}V265A and e{open}L269F). We confirm that only mutations in the e{open} subunit altered Ca2+ permeability of AChR-channels, with e{open}L269F increasing Pf (10% vs. 7% of wild type AChR) and e{open}I257F decreasing it (to 4.6%). We also found that, for e{open}L269F-AChR, the Ca2+ permeability and ACh-induced cell death can be normalized by clinically relevant concentrations of salbutamol or verapamil, providing the first evidence that the Ca2+ permeability of AChR-channels can be modulated and this treatment may provide protection against excitotoxic insults.

Original languageEnglish
Pages (from-to)272-278
Number of pages7
JournalCell Calcium
Volume49
Issue number4
DOIs
Publication statusPublished - Apr 2011

Keywords

  • Calcium permeability
  • Excitotoxicity
  • Fractional calcium current
  • Nicotinic acetylcholine receptor
  • Slow channel congenital myasthenic syndrome

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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