The pulmonary neuroendocrine cell (PNEC) system consists of solitary cells and distinctive cell clusters termed neuroepithelial bodies (NEB) localized in the airway epithelium. PNEC/NEB express a variety of bioactive substances, including amine (serotonin, 5HT) and neuropeptides. We have previously shown that NEB cells are O(2) sensors expressing nicotinamide adenine diphosphate oxidase complex and O(2) sensitive K(+) channel. Recently, we demonstrated expression of functional cystic fibrosis transmembrane conductance regulator (CFTR) and Cl(-) conductances in NEB cells of rabbit neonatal lung. Because PNEC/NEB are sparsely distributed and difficult to study in native lung, we investigated small-cell lung carcinoma (SCLC) and carcinoid tumor cell lines (tumor counterparts of normal PNEC/NEB) as models for PNEC/NEB. SCLC (H146, H345) and carcinoid (H727) cell lines express neuroendocrine cell markers, including chromogranin A, neural cell adhesion molecule (N-CAM), 5HT, and tryptophan hydroxylase. We report that H146, H345, and H727 express CFTR messenger RNA (reverse transcription polymerase chain reaction) and protein (immunoblotting) and possess functional CFTR Cl(-) conductance, demonstrated by an iodide efflux assay inhibitable by transfection with antisense CFTR. Using an immunoassay to quantitate 5HT secretion, we also show that downregulation of CFTR abolishes hypoxia-induced 5HT release, and reduces secretory response to high potassium. Our findings suggest that CFTR may modulate neurosecretory activity of PNEC/NEB possessing O(2) sensor function. We propose that these tumor cell lines may be useful models for investigating the role of CFTR in PNEC/NEB functions in health and disease.