Lambert–Eaton myasthenic syndrome: mouse passive‐transfer model illuminates disease pathology and facilitates testing therapeutic leads
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 the...
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Published in | Annals of the New York Academy of Sciences Vol. 1412; no. 1; pp. 73 - 81 |
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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. |
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AbstractList | 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. 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. |
Author | Ojala, Kristine S. Valdomir, Guillermo Wipf, Peter Tarr, Tyler B. Wu, Man Garcia‐Ocaña, Adolfo Meriney, Stephen D. Li, Yizhi Lacomis, David Liang, Mary |
AuthorAffiliation | 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 3 Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 2 Departments of Neurology and Pathology, Division of Neuromuscular Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania |
AuthorAffiliation_xml | – name: 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania – name: 3 Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, New York – name: 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania – name: 2 Departments of Neurology and Pathology, Division of Neuromuscular Diseases, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania |
Author_xml | – sequence: 1 givenname: Stephen D. surname: Meriney fullname: Meriney, Stephen D. email: meriney@pitt.edu organization: University of Pittsburgh – sequence: 2 givenname: Tyler B. surname: Tarr fullname: Tarr, Tyler B. organization: University of Pittsburgh – sequence: 3 givenname: Kristine S. surname: Ojala fullname: Ojala, Kristine S. organization: University of Pittsburgh – sequence: 4 givenname: Man surname: Wu fullname: Wu, Man organization: University of Pittsburgh – sequence: 5 givenname: Yizhi surname: Li fullname: Li, Yizhi organization: University of Pittsburgh – sequence: 6 givenname: David surname: Lacomis fullname: Lacomis, David organization: University of Pittsburgh Medical Center – sequence: 7 givenname: Adolfo surname: Garcia‐Ocaña fullname: Garcia‐Ocaña, Adolfo organization: Icahn School of Medicine at Mount Sinai – sequence: 8 givenname: Mary surname: Liang fullname: Liang, Mary organization: University of Pittsburgh – sequence: 9 givenname: Guillermo surname: Valdomir fullname: Valdomir, Guillermo organization: University of Pittsburgh – sequence: 10 givenname: Peter surname: Wipf fullname: Wipf, Peter organization: University of Pittsburgh |
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Snippet | Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage‐gated calcium channels that provide the... Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage-gated calcium channels that provide the... Abstract Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder caused by antibodies directed against the voltage‐gated calcium channels that... |
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SubjectTerms | Acetylcholine Action potential active zone Antibodies Calcium Calcium channels Calcium channels (voltage-gated) Channel gating Channels GV‐58 Immunoglobulin G Ion flux Lambert-Eaton myasthenic syndrome Mice Muscle contraction Muscles Neuromuscular junctions Neurotransmitter release Potassium voltage‐gated calcium channels |
Title | Lambert–Eaton myasthenic syndrome: mouse passive‐transfer model illuminates disease pathology and facilitates testing therapeutic leads |
URI | https://onlinelibrary.wiley.com/doi/abs/10.1111%2Fnyas.13512 https://www.ncbi.nlm.nih.gov/pubmed/29125190 https://www.proquest.com/docview/1992333856/abstract/ https://search.proquest.com/docview/1963275047 https://pubmed.ncbi.nlm.nih.gov/PMC5790601 |
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