Specificity of Lambert-Eaton myasthenic syndrome immunoglobulin for nerve terminal calcium channels.
Lambert-Eaton Myasthenic Syndrome (LEMS) is a presynaptic, neuromuscular disorder characterized by impaired nerve-evoked release of ACh. Repetitive nerve stimulation, which increases the probability of quantal release, improves the transmission defect. An autoantibody to Ca2+ channels of presynaptic motor nerve terminals is thought to mediate the pathogenesis of this disease. The goal of the present study was to examine the specificity of LEMS autoantibodies for nerve terminal Ca2+ channels as compared to other voltage-sensitive ion channels in nerve terminals, and to determine if non-specific membrane damage contributed to the pathogenesis of LEMS. The ion channel specificity of LEMS autoantibody was assessed by comparing the ability of acute application of IgG isolated from the plasma of a patient with LEMS to reduce depolarization-dependent uptake of 45Ca2+ and 22Na+ into or efflux of 86Rb+ from rat forebrain synaptosomes. The clinical diagnosis of LEMS was confirmed electrophysiologically by treatment of mice for 30 days with plasma (1.5 ml/day) taken from this patient. Characteristic reduction of quantal content elicited at 1 Hz and facilitation at 20 Hz was observed in mice treated with LEMS plasma compared to those treated with control plasma. One s, K(+)-stimulated 45Ca2+ uptake was inhibited 36.5 +/- 14.5% and 44.5 +/- 9.8% by acute application of 2 and 4 mg/ml LEMS IgG, respectively; IgG from patients with small cell carcinoma of the lung (SCC) had no effect on 45Ca2+ entry. The same concentrations of LEMS IgG affected neither voltage-dependent uptake of 22Na+ into veratridine-depolarized synaptosomes nor 86Rb+ efflux from K(+)-depolarized synaptosomes.(ABSTRACT TRUNCATED AT 250 WORDS)
Hewett
S J
SJ
Department of Pharmacology/Toxicology, Michigan State University, East Lansing 48824-1317.
Atchison
W D
WD
D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D015220:Calcium Channels / Q000276:immunology*; D002132:Calcium Radioisotopes; D007074:Immunoglobulin G / Q000276:immunology*; D015624:Lambert-Eaton Myasthenic Syndrome / Q000097:blood / Q000276:immunology*; D008297:Male; D008566:Membranes / Q000276:immunology; D009469:Neuromuscular Junction / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012414:Rubidium Radioisotopes; D012979:Sodium Radioisotopes; D013574:Synaptosomes / Q000276:immunology*
D015220:Calcium Channels; D002132:Calcium Radioisotopes; D007074:Immunoglobulin G; D018377:Neurotransmitter Agents; D012414:Rubidium Radioisotopes; D012979:Sodium Radioisotopes