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OBJECTIVE: To determine whether immunoglobulin G (IgG) from patients with Lambert-Eaton myasthenic syndrome (LEMS) decreases action potential–evoked synaptic vesicle exocytosis,and whether the effect is mediated by P/Q-type voltage-gated calcium channels (VGCCs). METHODS: IgG was obtained from 4 patients with LEMS (3 males, 1 female), including 2 patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all 4 patients, and against N-type VGCCs in 2. We incubated neuronal cultures with LEMS IgG and determined the size of the total recycling pool of synaptic vesicles and the rate of action potential–evoked exocytosis using fluorescence imaging of the amphiphilic dye SynaptoRed C1. Pooled IgG from healthy volunteers was used as a control. We repeated the experiments on synapses lacking P/Q-type calcium channels from a Cacna1a knockout mouse to determine whether these channels account for the pathogenic effect of LEMS IgG. RESULTS: LEMS IgG had no effect on the total recycling pool size but significantly reduced the rate of action potential–evoked synaptic exocytosis in wild-type neurons when compared with neurons treated with control IgG. In contrast, LEMS IgG had no effect on the rate of synaptic vesicle exocytosis in neurons lacking P/Q-type channels. CONCLUSIONS: These data provide direct evidence that LEMS IgG inhibits neurotransmitter release by acting on P/Q-type VGCCs.

Original publication

DOI

10.1212/WNL.0000000000001225

Type

Journal article

Journal

Neurology

Publication Date

10/02/2015

Volume

84

Pages

575 - 579

Keywords

Action Potentials, Adult, Aged, Animals, Autoantibodies, Calcium Channel Blockers, Calcium Channels, Calcium Channels, N-Type, Exocytosis, Female, Fluorescent Dyes, Humans, Immunoglobulin G, Lambert-Eaton Myasthenic Syndrome, Male, Mice, Mice, Knockout, Middle Aged, Neurons, Synaptic Transmission