Synaptotagmin can cause an immune-mediated model of Lambert-Eaton myasthenic syndrome in rats.

The possible antigenicity of synaptotagmin, a synaptic vesicle protein acting as a cooperative calcium (Ca2+) receptor in exocytosis, was tested to determine whether it is involved in the induction of Lambert-Eaton myasthenic syndrome in which antibodies against voltage-dependent Ca2+ channels or related molecules play a pathogenic role. Repeated injections to Lewis rats with peptides of synaptotagmin residues 20 through 53 or 1 through 30 that are presumably exposed at the nerve terminal surface during exocytosis induced corresponding antipeptide antibodies; on immunoblots, antibodies recognized synaptotagmin that was expressed in the clonal cells. Electrophysiologically, the peptide (residues 20-53)-immunized rats showed (1) reduced acetylcholine quantal content of end-plate potential, (2) an increase in quantal content at high extracellular Ca2+ concentration, and (3) early facilitation followed by less marked depression of end-plate potential amplitude at a tetanic rate of repetitive nerve stimulation. Findings are similar to those in human Lambert-Eaton myasthenic syndrome and passively transferred Lambert-Eaton myasthenic syndrome in mice, and thus suggest that antibody to a synaptotagmin-voltage-dependent Ca2+ channel complex may be involved in the pathogenesis of Lambert-Eaton myasthenic syndrome. The peptide (residues 1-30)-immunized rats showed no electrophysiological abnormality.