Lambert‐eaton myasthenic syndrome immunoglobulins react with multiple types of calcium channels in small‐cell lung carcinoma

Abstract

Barium currents through voltage-gated calcium (Ca2+) channels were studied in the small-cell lung carcinoma cell line NCI-H345 using patch clamp techniques. Pharmacological dissection of whole-cell barium currents revealed that 23% of the current was sensitive to nitrendipine, 35% to omega-conotoxin GVIA, and between 10 and 39% to omega-Aga-IVA. This implies that these cells express L-, N-, and P-type calcium channels. Only large cells expressed current that was sensitive to omega-Aga-IVA. The size dependency of this P-type channel expression may reflect the cell cycle stage. Cell-attached recordings revealed three unitary conductances: 5 to 6 pS, 10 to 12 pS, and 20 to 23 pS. The largest conductance channel (20-23 pS) was sensitive to Bay K 8644 and is presumed to represent L-type calcium channels. The frequency of observing the medium conductance channel (10-12 pS) was reduced by exposure to omega-conotoxin GVIA and may represent N-type channels. Incubation of cells with Lambert-Eaton myasthenic syndrome IgG for 24 to 48 hours removed up to 71% of the whole-cell current. Incubation with control human IgG (normal or myasthenia gravis) had no effect. Lambert-Eaton myasthenic syndrome IgG did not selectively target one "presynaptic" type of calcium channel, but rather appeared to target many of the calcium channel types that are expressed on small-cell lung carcinoma cells.

Human autoantibodies specific for the α 1A calcium channel subunit reduce both P-type and Q-type calcium currents in cerebellar neurons

“…Antibodies to this intracellular subunit would not be expected to cause functional effects on VDCCs in living cells. Previous workers (28)(29)(30) have shown that LEMS IgG blocks both P-type and N-type VDCCs in a human SCLC cell line and N-type and L-type VDCCs in human neuroblastoma cell lines. However, the data presented here suggest that the ␣ 1B subunit is not a general target of antibodies in a clinically representative sample of six LEMS patients.…”

Small Cell Lung Cancer

“…Patients with the Lambert-Eaton syndrome present with proximal leg weakness that is caused by antibodies directed against the voltage-gated calcium channels. 25,26 Paraneoplastic encephalomyelitis and sensory neuropathy are caused by the production of an antibody (anti-Hu) that cross-reacts with both small cell carcinoma antigens and human neuronal RNA-binding proteins, resulting in multiple neurologic deficits. 27 SCLC cells also can produce numerous polypeptide hormones, including adrenocorticotropic hormone (ACTH) and vasopressin (ADH), which cause Cushing syndrome and hyponatremia of malignancy, respectively.…”

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

“…VGCCs are composed of a number of pharmacologically and electrophysiologically distinct subtypes. Although antibodies have been described that bind to the L-, N-and P-/Q-VGCC subtypes (Meriney et al 1996), only those directed against the P-/Q-subtype, which is responsible for pre-synaptic neurotransmitter release at the neuromuscular junction, have been shown to be pathogenic (Pinto et al 1998).…”