The Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease that is often associated with lung cancer which shares a common antigenic protein with the motor nerve terminal. The myasthenic weakness is caused by an antibody-induced reduction in the release of acetylcholine from the nerve terminal. This study was undertaken to determine the target of LEMS antibodies and specify the voltage-gated calcium channel (VGCC) through which calcium influxes following the presynaptic membrane depolarization. Among the 5 types of VGCC, we found that the P/Q-type was highly recognized by LEMS antibodies. Using synthetic peptides or recombinant proteins as antigens for testing LEMS patients' sera or inducing an animal model of LEMS, we specified the S5-S6 linker regions in 3 of 4 domains constituting the alpha1 subunit of P/Q-type VGCC as immunodominant sites. Synaptotagmin, one of the functionally VGCC-associated proteins and a protein functioning as a calcium sensor for exocytosis of synaptic vesicles, was also found to be a pathogenic immunogen of LEMS when the recombinant protein for antibody assay and the synthetic peptide for the induction of animal model were used as antigens. The present study forms a united front against cancer and cancer-related myasthenic syndrome.