The Lambert-Eaton myasthenic syndrome (LEMS) is a disease of neuromuscular 
transmission in which autoantibodies against the P/Q-type voltage-gated calcium 
channel (VGCC) at the presynaptic nerve terminal play a major role in decreasing 
quantal release of acetylcholine (ACh), resulting in skeletal muscle weakness 
and autonomic symptoms. It is associated with cancer, particularly small-cell 
lung carcinoma (SCLC), in 50-60% of LEMS patients; the nerve terminal and 
carcinoma cells apparently share a common antigen (VGCC), suggesting an 
immunological cross-reactivity that may lead to the neurological abnormality. 
Non-tumor LEMS has a strong association with HLA-DR3-B8. In approximately 15% of 
LEMS patients, no anti-P/Q-type VGCC antibodies are found, suggesting 
recognition of other targets(s). The VGCC-associated protein synaptotagmin could 
be one candidate, because it acts as an exocytotic calcium receptor, is 
implicated in fast ACh release; its N-terminus is exposed extracellularly during 
exocytosis and it is expressed in SCLC. Antibodies against synaptotagmin-1 were 
detected in both anti-VGCC-positive and -negative LEMS patients (20%), and it 
can be immunogenic, allowing induction of an animal model of LEMS. Another 
candidate target is the M1-type presynaptic muscarinic ACh receptor (M1 mAChR), 
also expressed extracellularly on motor nerve terminals; it modulates 
cholinergic transmission, linking to P/Q-type VGCC. In our series of 25 LEMS 
patients with and without SCLC, anti-M1 mAChR antibodies were prevalent in both 
anti-VGCC-positive and -negative LEMS patients. Autonomic symptoms seemed more 
frequent in the latter; serum from one of them passively transferred LEMS-type 
electrophysiological defects to mice. As a compensatory mechanism, researchers 
in Oxford suggested a shift in the dependence of ACh release from the P/Q-type 
to other types of VGCC. We have also focused on G protein-coupled mAChRs and 
neurotrophins, which may affect both P/Q-type VGCC and clathrin-independent 
"kiss-and-run" synaptic vesicle recycling (fast-mode of endocytosis) via protein 
kinase C activation. We hypothesize that these signaling cascades help to 
compensate for the immune-mediated defects in calcium entry in LEMS, 
compensation that may frequently be restricted by the coincident anti-M1 mAChR 
antibodies in this disease.