Lambert-Eaton myasthenic syndrome (LES) is an acquired disorder of neuromuscular transmission frequently associated with small-cell carcinoma of the lung. The defect in this syndrome is primarily presynaptic, characterized by an inability of the motor nerve terminals to release a normal number of acetylcholine (ACh) quanta in response to a nerve impulse. Recent clinical and experimental studies of LES have achieved a sizeable advance toward understanding of the disease process. LES is now recognized as an autoimmune disease and an animal model based on passively transferred autoantibodies has been developed, which closely reproduces the human condition. The long-term objectives of our proposed study are to understand the subsynaptic mechanisms of the disease responsible for presynaptic impairment and to study the electrophysiological characteristics of LES autoantibodies and their apparent presynaptic antigenic recognition sites. We will pursue five specific aims: (1) further characterize the murine passive transferred LES and establish its validity as an animal model; (2) evaluate the Ca2+ sensitivity and pharmacology of the termial release process in murine LES and experimentally verify the hypothesis of reduced Ca2+ entry vs. reduced ACh release sites as a pathophysiologic mechanism of the presynaptic defect; (3) directly measure the inward Ca2+ currents at the control and murine LES motor nerve terminals; (4) elucidate the mechanism by which maitotoxin (MTX) induces a massive increase of quantal transmitter release; and (5) determine the in vitro effects of LES antibodies on prolactin release from rat anterior pituitary glands. The experimental techniques to be used include intra- and extracellular recording of the pre- and postsynaptic events of the neuromuscular junction and standard double antibody radioimmunoassay to accomplish the determination of hormone concentration.
| Viglione, M P; O'Shaughnessy, T J; Kim, Y I (1995) Inhibition of calcium currents and exocytosis by Lambert-Eaton syndrome antibodies in human lung cancer cells. J Physiol 488 ( Pt 2):303-17 |
| Viglione, M P; Creutz, C E; Kim, Y I (1992) Lambert-Eaton syndrome: antigen-antibody interaction and calcium current inhibition in chromaffin cells. Muscle Nerve 15:1325-33 |
