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Ann N Y Acad Sci. 2018 Jan;1412(1):73-81. doi: 10.1111/nyas.13512. Epub 2017 Nov 10.

Lambert-Eaton myasthenic syndrome: mouse passive-transfer model illuminates disease pathology and facilitates testing therapeutic leads.

Author information

  • 1Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • 2Division of Neuromuscular Diseases, Departments of Neurology and Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • 3Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the calcium ion flux that triggers acetylcholine release at the neuromuscular junction. To study the pathophysiology of LEMS and test candidate therapeutic strategies, a passive-transfer animal model has been developed in mice, which can be created by daily intraperitoneal injections of LEMS patient serum or IgG into mice for 2-4 weeks. Results from studies of the mouse neuromuscular junction have revealed that each synapse has hundreds of transmitter release sites but that the probability for release at each one is likely to be low. LEMS further reduces this low probability such that transmission is no longer effective at triggering a muscle contraction. The LEMS-mediated attack reduces the number of presynaptic calcium channels, disorganizes transmitter release sites, and results in the homeostatic upregulation of other calcium channel types. Symptomatic treatment is focused on increasing the probability of release from dysfunctional release sites. Current treatment uses the potassium channel blocker 3,4-diaminopyridine (DAP) to broaden the presynaptic action potential, providing more time for calcium channels to open. Current research is focused on testing new calcium channel gating modifiers that work synergistically with DAP.

KEYWORDS:

GV-58; Lambert-Eaton myasthenic syndrome; active zone; voltage-gated calcium channels

PMID:
29125190
PMCID:
PMC5790601
[Available on 2019-01-01]
DOI:
10.1111/nyas.13512
[PubMed - in process]
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