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Antagonism of Voltage-gated Calcium Channels in Small Cell Carcinomas of Patients with and without Lambert-Eaton Myasthenic Syndrome by Autoantibodies -Conotoxin and Adenosine¹

Neuroimmunology Laboratory, Departments of Immunology and Neurology, Mayo Clinic, Rochester, MN 55905 [H. J. D., G. E. G., V. A. L.]; Department of Neurology, University of Minnesota, Minneapolis, MN 55455 [E. H. L.]; and Department of Biology, University of Utah, Salt Lake City, UT 84112 [B. M. O.]

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 -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 -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.

¹ This investigation was supported by NIH Grants CA37343 (V. A. L.), NS-23691 (E. H. L.), and GM22737 (B. M. O.).

² To whom requests for reprints should be addressed, at Room 828, Guggenheim Building, Mayo Clinic, Rochester, MN 55905.

Received 1/ 4/88. Revised 4/ 7/88. Revised 5/19/88. Accepted 5/27/88.

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