Lambert-Eaton myasthenic syndrome as an autoimmune calcium-channelopathy

Lambert-Eaton myasthenic syndrome (LEMS), often associated with small cell lung carcinoma (SCLC), is a disease of neuromuscular transmission in which antibodies directed against voltage-gated calcium channel (VGCC) in the motor nerve terminal play a crucial role in causing a deficient quantal release of acetylcholine. We focused attention on the P/Q-type VGCC, against which a majority of LEMS patients carry the specific antibody. Since the P/Q-type VGCC expresses in SCLC, the motor nerve terminal and SCLC may share a common VGCC antigen. In search for antigenic sites at the molecular level, We employed peptides or recombinant protein corresponding to the S5-S6 linker of each of four domains forming the alpha 1A subunit and tested their antigenicity. As the result, we specified the domain II, III and IV as immunodominant sites by the induction of an immune-mediated animal model of LEMS and the assay for antibodies in LEMS patients. Also, by use of peptides or recombinant protein corresponding to the synaptotagmin I, we found that in this VGCC-associated protein, the segment which exposes extracellularly during exocytosis can be antigenic for LEMS.