Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
J Neurosci
2002 Aug 01;2215:6447-57. doi: 20026643.
Show Gene links
Show Anatomy links
Active calcium accumulation underlies severe weakness in a panel of mice with slow-channel syndrome.
Gomez CM, Maselli RA, Groshong J, Zayas R, Wollmann RL, Cens T, Charnet P.
???displayArticle.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.
Bertrand,
Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal alpha 7 nicotinic receptor.
1993, Pubmed,
Xenbase
Bertrand,
Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal alpha 7 nicotinic receptor.
1993,
Pubmed
,
Xenbase Bhattacharyya,
Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents.
1997,
Pubmed Bodensteiner,
Intracellular calcium accumulation in Duchenne dystrophy and other myopathies: a study of 567,000 muscle fibers in 114 biopsies.
1978,
Pubmed Boulter,
Isolation of a clone coding for the alpha-subunit of a mouse acetylcholine receptor.
1985,
Pubmed Brenner,
Imprinting of acetylcholine receptor messenger RNA accumulation in mammalian neuromuscular synapses.
1990,
Pubmed Brini,
A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency.
1999,
Pubmed Charnet,
Structure of the gamma-less nicotinic acetylcholine receptor: learning from omission.
1992,
Pubmed
,
Xenbase Choi,
Excitotoxic cell death.
1992,
Pubmed Choi,
Calcium and excitotoxic neuronal injury.
1994,
Pubmed Croxen,
Mutations in different functional domains of the human muscle acetylcholine receptor alpha subunit in patients with the slow-channel congenital myasthenic syndrome.
1997,
Pubmed
,
Xenbase Decker,
Calcium permeability of the nicotinic acetylcholine receptor: the single-channel calcium influx is significant.
1990,
Pubmed Engel,
New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome.
1996,
Pubmed Engel,
A newly recognized congenital myasthenic syndrome attributed to a prolonged open time of the acetylcholine-induced ion channel.
1982,
Pubmed Evans,
The entry of labelled calcium into the innervated region of the mouse diaphragm muscle.
1974,
Pubmed Fenster,
Regulation of alpha4beta2 nicotinic receptor desensitization by calcium and protein kinase C.
1999,
Pubmed
,
Xenbase Filatov,
The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating.
1995,
Pubmed
,
Xenbase Gardner,
Nucleotide sequence of the epsilon-subunit of the mouse muscle nicotinic acetylcholine receptor.
1990,
Pubmed Gomez,
A transgenic mouse model of the slow-channel syndrome.
1996,
Pubmed
,
Xenbase Gomez,
Genetic manipulation of AChR responses suggests multiple causes of weakness in slow-channel syndrome.
1998,
Pubmed Gomez,
Novel delta subunit mutation in slow-channel syndrome causes severe weakness by novel mechanisms.
2002,
Pubmed
,
Xenbase Gomez,
Slow-channel transgenic mice: a model of postsynaptic organellar degeneration at the neuromuscular junction.
1997,
Pubmed
,
Xenbase Gomez,
A beta-subunit mutation in the acetylcholine receptor channel gate causes severe slow-channel syndrome.
1996,
Pubmed Gomez,
Induction of the morphologic changes of both acute and chronic experimental myasthenia by monoclonal antibody directed against acetylcholine receptor.
1984,
Pubmed Gomez,
A leucine-to-phenylalanine substitution in the acetylcholine receptor ion channel in a family with the slow-channel syndrome.
1995,
Pubmed Gorman,
The Rous sarcoma virus long terminal repeat is a strong promoter when introduced into a variety of eukaryotic cells by DNA-mediated transfection.
1982,
Pubmed Gunter,
Transport of calcium by mitochondria.
1994,
Pubmed Hartmann,
Disturbances of the neuronal calcium homeostasis in the aging nervous system.
1994,
Pubmed Imoto,
A ring of uncharged polar amino acids as a component of channel constriction in the nicotinic acetylcholine receptor.
1991,
Pubmed
,
Xenbase Johnson,
Muscle creatine kinase sequence elements regulating skeletal and cardiac muscle expression in transgenic mice.
1989,
Pubmed Kashiwa,
Calcium phosphate in osteogenic cells. A critique of the glyoxal bis(2-hydroxyanil) and the dilute silver acetate methods.
1970,
Pubmed Kawabuchi,
Neostigmine myopathy is a calcium ion-mediated myopathy initially affecting the motor end-plate.
1982,
Pubmed Köhr,
Endogenous intracellular calcium buffering and the activation/inactivation of HVA calcium currents in rat dentate gyrus granule cells.
1991,
Pubmed LaPolla,
Isolation and characterization of a cDNA clone for the complete protein coding region of the delta subunit of the mouse acetylcholine receptor.
1984,
Pubmed Lerche,
Ion channels and epilepsy.
2001,
Pubmed Martinez-Serrano,
Calcium binding to the cytosol and calcium extrusion mechanisms in intact synaptosomes and their alterations with aging.
1992,
Pubmed Maselli,
Anconeus muscle: a human muscle preparation suitable for in-vitro microelectrode studies.
1991,
Pubmed Maselli,
Effects of a monoclonal anti-acetylcholine receptor antibody on the avian end-plate.
1989,
Pubmed Mayer,
The physiology of excitatory amino acids in the vertebrate central nervous system.
1987,
Pubmed Merlie,
Concentration of acetylcholine receptor mRNA in synaptic regions of adult muscle fibres.
,
Pubmed Milone,
Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor alpha subunit.
1997,
Pubmed Namba,
Staining for nerve fiber and cholinesterase activity in fresh frozen sections.
1967,
Pubmed Nojima,
The evidence of accelerative interaction between cAMP-dependent protein kinase and external calcium for the desensitization of nicotinic acetylcholine receptor channel in mouse skeletal muscle cells.
1994,
Pubmed Ochoa,
Desensitization of the nicotinic acetylcholine receptor: molecular mechanisms and effect of modulators.
1989,
Pubmed Oosterhuis,
The slow channel syndrome. Two new cases.
1987,
Pubmed Pestronk,
Measurement of junctional acetylcholine receptors in myasthenia gravis: clinical correlates.
1985,
Pubmed Satrústegui,
Cytosolic and mitochondrial calcium in synaptosomes during aging.
1996,
Pubmed Schwartz,
Concentration and localization of calcium in frog gastric mucosa.
1967,
Pubmed Siara,
Human nicotinic acetylcholine receptor: the influence of second messengers on activation and desensitization.
1990,
Pubmed Steinlein,
Genes and mutations in idiopathic epilepsy.
2001,
Pubmed Taketo,
FVB/N: an inbred mouse strain preferable for transgenic analyses.
1991,
Pubmed Tamamizu,
Alteration in ion channel function of mouse nicotinic acetylcholine receptor by mutations in the M4 transmembrane domain.
1999,
Pubmed
,
Xenbase Wasniewska,
Abnormal calcium homeostasis in fibroblasts from patients with Leigh disease.
2001,
Pubmed
