Voltage-gated calcium channels in small-cell lung carcinomas may initiate autoimmunity in the paraneoplastic neuromuscular disorder Lambert—Eaton syndrome. The calcium-channel subtype that is responsible is not known. We compared the effects of antagonists of L-type, N-type, and P/Q-type neuronal calcium channels on the depolarization-dependent influx of calcium-45 in cultured carcinoma cells. Serum samples from patients with various disorders were tested for reactivity with P/Q-type channels solubilized from carcinoma and cerebellar membranes and N-type channels from cerebral cortex. P/Q-type calcium-channel antagonists were the most potent inhibitors of depolarization-induced 45Ca influx in cultured small-cell carcinoma cell lines. Anti—P/Q-type calcium-channel antibodies were found in serum from all 32 patients with the Lambert—Eaton syndrome and a diagnosis of cancer and in 91 percent of the 33 patients with the Lambert—Eaton syndrome without cancer. Anti—N-type calcium-channel antibodies were found in 49 percent of the 65 patients with the Lambert—Eaton syndrome. Lower titers of anti—P/Q-type and anti—N-type calcium-channel antibodies were found in 54 percent of 70 patients with a paraneoplastic encephalomyeloneuropathic complication of lung, ovarian, or breast carcinoma, 24 percent of 90 patients with cancer but no evident neurologic complications, 23 percent of 78 patients with sporadic amyotrophic lateral sclerosis, and less than 3 percent of 69 patients with myasthenia gravis, epilepsy, or scleroderma. The high frequency of P/Q-type calcium-channel antibodies found in patients with the Lambert—Eaton syndrome implies that antibodies of this specificity have a role in the presynaptic pathophysiology of this disorder.
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