Spillane, J; Ermolyuk, Y; Cano-Jaimez, M; Lang, B; Vincent, A; Volynski, KE; Kullmann, DM; Lambert-Eaton syndrome IgG inhibits transmitter release via P/Q Ca²⁺ channels. Neurology , 84 (6) pp. 575-579. 10.1212/WNL.0000000000001225.

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Abstract

Objective: To determine whether immunoglobulin G (IgG) from patients with Lambert Eaton 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 four patients with LEMS (3M, 1F), including two patients with lung malignancy. Antibodies against P/Q-type VGCCs were detected in all four patients, and Ntype in two. 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 to 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.

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