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Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of neuromuscular transmission in which antibodies are directed against voltage-gated calcium channels (VGCCs). We studied the action of LEMS immunoglobulin G (IgG) on cloned human VGCCs stably transfected into human embryonic kidney cells (HEK293). All LEMS IgGs tested bound to the surface of the P/Q-type VGCC cell line and caused a significant reduction in whole-cell calcium currents in these cells. By contrast, only 2 out of 6 IgGs bound extracellularly to the N-type VGCC cell line, and none of the LEMS IgGs tested was able to reduce whole-cell calcium currents in these cells. We used this apparent specificity of LEMS IgG for the P/Q-type VGCC to investigate the action of these IgGs on model systems where a number of different VGCC populations exist in equilibrium. LEMS IgG caused a significant downregulation in the omega-agatoxin IVA-sensitive P/Q-type VGCCs of cultured rat cerebellar neurons, but this was accompanied by a concomitant rise in the "resistant" R-type VGCCs. By using the passive transfer model of LEMS, similar results were observed at the mouse neuromuscular junction, where a significant reduction in P/Q-type VGCCs was paralleled by an increase in L- and R-type VGCCs. These results demonstrate an unexpected plasticity in the expression of VGCCs in mammalian neurons and may represent a mechanism by which the pathogenic effects of LEMS IgG are reduced.

Type

Journal article

Journal

Ann N Y Acad Sci

Publication Date

09/2003

Volume

998

Pages

187 - 195

Keywords

Action Potentials, Animals, Autoantibodies, Calcium Channel Blockers, Calcium Channels, Cells, Cultured, Dose-Response Relationship, Drug, Electrophysiology, Embryo, Mammalian, Evoked Potentials, Humans, Immunoglobulin gamma-Chains, Lambert-Eaton Myasthenic Syndrome, Neuromuscular Junction, Precipitin Tests, Purkinje Cells, Transfection