Lambert-Eaton myasthenic syndrome is an
autoimmune disease that impairs neuromuscular transmission. Several studies suggest that
neurotransmitter release is reduced by an immune response directed against the
calcium channel complex of nerve terminals. The
immunoglobulin G fractions from
Lambert-Eaton myasthenic syndrome patients immunoprecipitate solubilized neuronal N- and P/Q-type channels and in certain cases brain, skeletal and cardiac muscle L-type channels [El Far O. et al. (1995) J. Neurochem. 64, 1696-1702; Lennon V. A. and Lambert E. H. (1989) Mayo Clin. Proc. 64, 1498-1504; Sher E. et al. (1989) Lancet ii, 640-643; Suenaga A. et al. (1996) Muscle Nerve 19, 1166-1168]. These channel immunoprecipitation assays are considered as useful for the diagnosis of this syndrome. In this study, we demonstrate that two predominant neuronal
voltage-dependent calcium channel beta subunits (beta3 and beta4, of mol. wt 58,000) are general targets of
Lambert-Eaton myasthenic syndrome autoantibodies. Of 20 disease sera tested, 55% were able to immunoprecipitate 35S-labeled beta subunits. All five patients affected with
small-cell lung carcinoma were positive for the beta-subunit immunoprecipitation assay. Interestingly, only a fraction of the beta-subunit-positive sera was also able to immunoprecipitate N- and P/Q-type channels, suggesting that several of the beta-subunit
epitopes are masked in native channels. In accordance with this observation, we found that several beta-positive sera were able to prevent the interaction between
calcium channel alpha1 and beta subunits in vitro. In cases where sera were able to immunoprecipitate beta subunits, N- and P/Q-type channels, the immunoprecipitation of both channel types was either partially or entirely mediated by beta-subunit
antibodies. Our results suggest that assays based on the immunoprecipitation of beta subunits can be used as an additional test to assist in the diagnosis of
Lambert-Eaton myasthenic syndrome.