Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells

Abstract

Pulmonary neuroendocrine cells (PNECs) have been implicated in the development of small cell lung carcinoma (SCLC) and pediatric asthma, and smoking is a risk factor for both diseases. We as well as others have shown that the α7 nicotinic acetylcholine receptor (α 7 nAChR) regulates the release of 5-hydroxytryptamine (5-HT, serotonin) in PNECs and SCLC. Serotonin is an autocrine, growth factor for PNECs and SCLC and acts as bronchoconstrictor. We found that nicotine and its nitrosated carcinogenic derivative 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) bind to the α 7 nAChR in SCLC and PNECs, resulting in the influx of Ca 2+, release of 5-HT, and activation of a mitogenic pathway mediated by protein kinase C (PKC), Raf-1, mitogen activated protein kinase (MAPK) and c-myc. Exposure to 10% CO2 acted synergistically. Unstimulated SCLC cells from smokers demonstrated high base levels of 5-HT release and of individual downstream signaling components in comparison to PNECs. Subchronic exposure of PNECs to NNK up-regulated the α7 nAChR and its associated serotonergic mitogenic pathway in PNECs, an effect that may contribute to the development of SCLC in smokers and pediatric asthma in children of mothers who smoke. © 2003 Wiley-Liss, Inc.