Antagonism of voltage-gated calcium channels in small cell carcinomas of patients with and without Lambert-Eaton myasthenic syndrome by autoantibodies omega-conotoxin and adenosine.
The Lambert-Eaton myasthenic syndrome (LES) is an autoimmune presynaptic disorder of peripheral cholinergic neurotransmission in which there is often an associated small cell lung carcinoma (SCC). SCC lines established from patients with and without LES exhibit a Ca2+ influx response to depolarization by K+ that is consistent with the presence of voltage-gated Ca2+ channels. Autoantibodies antagonistic to SCC Ca2+ channel activity were found exclusively in patients with LES, independent of cancer status. Depolarization-induced uptake of 45Ca2+ by SCC lines was reduced maximally after 3-4 days of exposure to serum immunoglobulins from 14 of 19 LES patients, while 53 control immunoglobulins (including patients with SCC, other tumors, other paraneoplastic syndromes, and other neurological and autoimmune diseases) were without effect. The snail neurotoxin omega-conotoxin of subtype GVIA, which is a specific antagonist of presynaptic Ca2+ channels, inhibited K+-stimulated Ca2+ uptake in a dose-dependent manner that was essentially irreversible. Adenosine, reported to be a specific antagonist of neuronal Ca2+ channels, also impaired voltage-stimulated Ca2+ influx in SCC. Use of LES patients' IgG and omega-conotoxin in further studies of SCC may facilitate identification and purification of the LES antigen(s) and yield a quantitative serological test for diagnosing this autoimmune paraneoplastic syndrome.
De Aizpurua
H J
HJ
Department of Immunology, Mayo Clinic, Rochester, MN 55905.
Lambert
E H
EH
Griesmann
G E
GE
Olivera
B M
BM
Lennon
V A
VA
D000241:Adenosine / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007473:Ion Channels / Q000187:drug effects*; D008175:Lung Neoplasms / Q000378:metabolism*; D008978:Mollusk Venoms / Q000494:pharmacology; D009135:Muscular Diseases / Q000378:metabolism*; D010257:Paraneoplastic Syndromes / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020866:omega-Conotoxin GVIA
D001323:Autoantibodies; D002121:Calcium Channel Blockers; D007074:Immunoglobulin G; D007473:Ion Channels; D008978:Mollusk Venoms; D020866:omega-Conotoxin GVIA; D000241:Adenosine; D002118:Calcium