Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome

Christopher M. Gomez, Ricardo A Maselli, Jason Groshong, Roberto Zayas, Robert L. Wollmann, Thierry Cens, Pierre Charnet

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Mutations affecting the gating and channel properties of ionotropic neurotransmitter receptors in some hereditary epilepsies, in familial hyperekplexia, and the slow-channel congenital myasthenic syndrome (SCCMS) may perturb the kinetics of synaptic currents, leading to significant clinical consequences. Although at least 12 acetylcholine receptor (AChR) mutations have been identified in the SCCMS, the altered channel properties critical for disease pathogenesis in the SCCMS have not been identified. To approach this question, we investigated the effect of different AChR subunit mutations on muscle weakness and the function and viability of neuromuscular synapses in transgenic mice. Targeted expression of distinct mutant AChR subunits in skeletal muscle prolonged the decay phases of the miniature endplate currents (MEPCs) over a broad range. In addition, both muscle strength and the amplitude of MEPCs were lower in transgenic lines with greater MEPC duration, SCCMS is associated with calcium overload of the neuromuscular junctional sarcoplasm. We found that the extent of calcium overload of motor endplates in the panel of transgenic mice was influenced by the relative permeability of the mutant AChRs to calcium, on the duration of MEPCs, and on neuromuscular activity. Finally, severe degenerative changes at the motor endplate (endplate myopathy) were apparent by electron microscopy in transgenic lines that displayed the greatest activity-dependent calcium overload, These studies demonstrate the importance of control of the kinetics of AChR channel gating for the function and viability of the neuromuscular junction.

Original languageEnglish (US)
Pages (from-to)6447-6457
Number of pages11
JournalJournal of Neuroscience
Volume22
Issue number15
StatePublished - Aug 1 2002

Keywords

  • Calcium
  • Degeneration
  • Kinetics
  • Mutation
  • Neuromuscular junction
  • Synaptic currents

ASJC Scopus subject areas

  • Neuroscience(all)

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    Gomez, C. M., Maselli, R. A., Groshong, J., Zayas, R., Wollmann, R. L., Cens, T., & Charnet, P. (2002). Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome. Journal of Neuroscience, 22(15), 6447-6457.