tetrodotoxin and Carcinoma--Small-Cell

Neuroepithelial bodies act as airway O2 sensors, but studies of their activity at the cellular level have been severely limited because they are present at such a low density in lung tissue. Small cell lung carcinoma (SCLC) cells are believed to be derived from neuroepithelial body cells and may represent a model system for investigating the mechanisms of airway chemoreception. Here we have used the whole cell patch-clamp technique to investigate the effects of acute hypoxia on voltage-gated ionic currents and membrane potential in H-146 SCLC cells. Step depolarizations evoked transient inward currents due to activation of Na+ and Ca2+ channels, followed by outward K+ currents. K+ currents were partially inhibited by 200 microM Cd2+ (indicative of the presence of a Ca2+-dependent component of the K+ current) and were inhibited by tetraethylammonium (TEA) in a concentration-dependent manner, although even at 100 mM TEA, a residual K+ current could be detected. Hypoxia (PO2 15-20 mmHg) caused a reversible inhibition of outward K+ currents without affecting inward currents. Inhibition by hypoxia was also observed in the presence of Cd2+. Hypoxia and TEA caused membrane depolarization in H-146 cells, and their effects appeared additive. These findings indicate that H-146 cells possess O2-sensitive, Ca2+-independent K+ channels that can influence cell membrane potential. SCLC cells may, therefore, represent a good model for investigating the mechanisms underlying O2 sensing by airway chemoreceptor cells.

Topics: Cadmium; Carcinoma, Small Cell; Cell Hypoxia; Epithelial Cells; Humans; Ion Channel Gating; Lung Neoplasms; Membrane Potentials; Oxygen; Potassium Channels; Tetraethylammonium; Tetrodotoxin; Tumor Cells, Cultured

Lambert-Eaton syndrome, an autoimmune disorder frequently associated with small-cell carcinoma of the lung, is characterized by impaired evoked release of acetylcholine from the motor nerve terminal. Immunoglobulin G (IgG) antibodies from patients with the syndrome, applied to bovine adrenal chromaffin cells, reduced the voltage-dependent calcium channel currents by about 40 percent. When calcium was administered directly into the cytoplasm, however, the IgG-treated cells exhibited normal exocytotic secretion, as assayed by membrane capacitance measurement. Measurement with the fluorescent calcium indicator fura-2 indicated that the IgG treatment reduced potassium-stimulated increase in free intracellular calcium concentration. The pathogenic IgG modified neither kinetics of calcium channel activation nor elementary channel activity, suggesting that a reduction in the number of functional calcium channels underlies the IgG-induced effect. Therefore, Lambert-Eaton syndrome IgG reacts with voltage-dependent calcium channels and blocks their function, a phenomenon that can account for the presynaptic impairment characteristic of this disorder.

Topics: Adrenal Glands; Autoantibodies; Autoimmune Diseases; Benzofurans; Calcium; Carcinoma, Small Cell; Cell Membrane; Chromaffin System; Electric Conductivity; Exocytosis; Fluorescent Dyes; Fura-2; Humans; Immunoglobulin G; Ion Channels; Lung Neoplasms; Neuromuscular Diseases; Sodium; Synapses; Syndrome; Tetrodotoxin