Antibodies against the beta subunit of voltage-dependent calcium channels in Lambert-Eaton myasthenic syndrome

Lambert-Eaton myasthenic syndrome is an autoimmune disease that impairs neu romuscular transmission. Several studies suggest that neurotransmitter rele ase is reduced by an immune response directed against the calcium channel c omplex of nerve terminals. The immunoglobulin G fractions from Lambert-Eato n myasthenic syndrome patients immunoprecipitate solubilized neuronal N- an d P/Q-type channels and in certain cases brain, skeletal and cardiac muscle L-type channels [EI Far O. et ai. (1995) J. Neurochem. 64, 1696-1702; Lenn on V. A. and Lambert E. H. (1989) Mayo Clin. Proc. 64, 1498-1504; Sher E. e t al. (1989) Lancet ii, 640-643; Suenaga A. et al. (1996) Muscle Nerve 19, 1166-1168]. These channel immunoprecipitation assays are considered as usef ul for the diagnosis of this syndrome. In this study, we demonstrate that t wo predominant neuronal voltage-dependent calcium channel beta subunits (be ta(3) and beta(4), of mel. wt 58,000) are general targets of Lambert-Eaton myasthenic syndrome autoantibodies. Of 20 disease sera tested, 55% were abl e to immunoprecipitate S-35-labeled beta subunits. All five patients affect ed with small-cell lung carcinoma were positive for the beta-subunit immuno precipitation assay. Interestingly, only a fraction of the beta-subunit-pos itive sera was also able to immunoprecipitate N- and P/Q-type channels, sug gesting that several of the beta-subunit epitopes are masked in native chan nels. In accordance with this observation, we found that several beta-posit ive sera were able to prevent the interaction between calcium channel alpha (1) and beta subunits in vitro. In cases where sera were able to immunoprec ipitate beta subunits, N- and P/Q-type channels, the immunoprecipitation of both channel types was either partially or entirely mediated by beta-subun it antibodies. Our results suggest that assays based on the immunoprecipitation of beta su bunits can be used as an additional test to assist in the diagnosis of Lamb ert-Eaton myasthenic syndrome. (C) 1999 IBRO. Published by Elsevier Science Ltd.