Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome.
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.
Gomez
Christopher M
CM
Department of Neurology, University of Minnesota, Minneapolis, Minnesota 55455, USA. gomez001@tc.umn.edu
Maselli
Ricardo A
RA
Groshong
Jason
J
Zayas
Roberto
R
Wollmann
Robert L
RL
Cens
Thierry
T
Charnet
Pierre
P
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004576:Electromyography; D018390:Gene Targeting; D051379:Mice; D008822:Mice, Transgenic; D009045:Motor Endplate / Q000378:metabolism / Q000473:pathology; D009119:Muscle Contraction / Q000235:genetics; D018908:Muscle Weakness / Q000209:etiology* / Q000378:metabolism*; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000209:etiology* / Q000503:physiopathology*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010539:Permeability; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D019076:Transgenes; D014981:Xenopus
D021122:Protein Subunits; D012333:RNA, Messenger; D011950:Receptors, Cholinergic; D002118:Calcium