Lambert-Eaton syndrome antibodies inhibit acetylcholine release and P/Q-type Ca2+ channels in electric ray nerve endings

• Published in: The Journal of physiology Vol. 508; no. 2; pp. 427 - 438
• Main Authors: Satoh, Yasushi, Hirashima, Naohide, Tokumaru, Hiroshi, Takahashi, Masanori P., Ang, Jin K, Viglione, Michael P., Kim, Yong I., Kirino, Yutaka
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15-04-1998; Blackwell Science Ltd; Blackwell Science Inc
• Subjects: Acetylcholine - metabolism; Animals; Antibodies - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Calcium Channels - metabolism; Chromaffin Cells - drug effects; Chromaffin Cells - metabolism; Down-Regulation - drug effects; Electric Organ - drug effects; Electric Organ - innervation; Electric Organ - metabolism; Electrophysiology; Humans; Immunoglobulin G - isolation & purification; Immunoglobulin G - pharmacology; In Vitro Techniques; Lambert-Eaton Myasthenic Syndrome - immunology; Lambert-Eaton Myasthenic Syndrome - metabolism; Membrane Potentials - drug effects; Membrane Potentials - physiology; Nerve Endings - drug effects; Nerve Endings - metabolism; Original; Patch-Clamp Techniques; Synaptosomes - drug effects; Synaptosomes - metabolism; Torpedo - metabolism
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1111/j.1469-7793.1998.427bq.x

The types of voltage-dependent calcium channels (VDCCs) present in the cholinergic terminals isolated from the electric organ
of the ray, Narke japonica , were characterized on the basis of their pharmacological sensitivity to specific antagonists. Inhibition of these channel
types by autoantibodies from patients with the Lambert-Eaton syndrome (LES) was then studied to determine the specificity
of the pathogenic IgG.
In normal untreated synaptosomal preparations, maximal doses of N- and P and/or Q-type Ca 2+ channel antagonists, ω-conotoxin GVIA and ω-agatoxin IVA, inhibited depolarization-evoked ACh release by 47% and 43%, respectively.
Calciseptine, an L-type VDCC antagonist, caused a 20% reduction in the release. This indicates that the exocytotic release
process is predominantly mediated by N- and P/Q-type VDCCs.
LES IgG or sera caused an inhibition of ACh release by 39-45% in comparison with the control antibody-treated preparations.
The ionomycin-induced ACh release, however, was not altered by the antibodies. Additionally, the same LES antibodies inhibited
whole-cell calcium currents ( I Ca ) in bovine adrenal chromaffin cells. Thus, the pathogenic antibodies exert their action on VDCCs present in the synaptosomes.
The efficacy of three Ca 2+ channel antagonists in blocking ACh release was determined in preparations pretreated with LES IgG. ω-Agatoxin IVA produced
only an additional 3-5% reduction in release beyond that obtained with LES antibodies. Despite the pretreatment with LES IgG,
ω-conotoxin GVIA and calciseptine inhibited the release to nearly their control levels.
These results indicate that LES antibodies mainly downregulate P/Q-type Ca 2+ channels which contribute to presynaptic transmitter release from the cholinergic nerve terminals of electric organ.
The present findings are consistent with the hypothesis that P/Q-type VDCCs at the neuromuscular junction are the target of
LES antibodies and that their inhibition by the antibodies produces the characteristic neuromuscular defect in this disease.