Cross-linking of presynaptic calcium channels: a mechanism of action for Lambert-Eaton myasthenic syndrome antibodies at the mouse neuromuscular junction.
Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission. Immunoglobulin G (IgG) autoantibodies act presynaptically to cause functional loss of Ca2+ channels by down-regulation. This in turn causes reduced release of acetylcholine in response to nerve stimulation (i.e. reduced quantal content). We show here that in vitro application of LEMS IgG for 24 h was as effective in causing reduced quantal content in mice as injecting animals with the antibody for 2 days. Furthermore, incubation with divalent (F(ab')2) fragments also significantly reduced quantal content. However, monovalent (Fab) fragments were without significant effect. No antibody or antibody fragment preparation affected spontaneous release. Whole LEMS IgG and F(ab')2 (but not Fab) fragments also inhibited K(+)-evoked 45Ca2+ flux in a small cell carcinoma cell line. These findings present functional evidence that LEMS IgG-induced down-regulation of nerve terminal Ca2+ channels arises due to antibody cross-linking of these channels.
Peers
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C
Department of Pharmacology, Leeds University, UK.
Johnston
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I
Lang
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Wray
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D
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000276:immunology*; D015220:Calcium Channels / Q000378:metabolism*; D004563:Electrochemistry; D004594:Electrophysiology; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology; D015624:Lambert-Eaton Myasthenic Syndrome / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D009469:Neuromuscular Junction / Q000276:immunology* / Q000503:physiopathology; D013569:Synapses / Q000378:metabolism*
D000906:Antibodies; D015220:Calcium Channels; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D000109:Acetylcholine