ACTIVATION OF DELTA-OPIOID RECEPTORS INHIBITS NEURONAL-LIKE CALCIUM CHANNELS AND DISTAL STEPS OF CA2-DEPENDENT SECRETION IN HUMAN SMALL-CELL LUNG-CARCINOMA CELLS()

Human small-cell lung carcinoma (SCLC) cells express neuronal-like vol tage-operated calcium channels (VOCCs) and release mitogenic hormones such as serotonin (5-HT). Opioid peptides, on the other hand, have bee n shown to reduce SCLC cell proliferation by an effective autocrine pa thway. Here we show that in GLC8 SCLC cells, only delta-opioid recepto r subtype mRNA is expressed. Consistently, the selective delta-opioid agonist [D-Pen(2)-Pen(5)]-enkephalin (DPDPE), but not mu and kappa ago nists, potently and dose-dependently inhibits high-threshold (HVA) VOC Cs in these cells. As in peripheral neurons, this modulation is largel y voltage-dependent, mediated by pertussis toxin (PTX)-sensitive G-pro teins, cAMP-independent, and mainly affecting N-type VOCCs. With the s ame potency and selectivity, DPDPE also antagonizes the Ca2+-dependent release of [H-3]serotonin ([H-3]5-HT) from GLC8 cells. However, DPDPE inhibits not only the depolarization-induced release, but also the Ca 2+-dependent secretion induced by thapsigargin or ionomycin. This sugg ests that besides inhibiting HVA VOCCs, opioids also exert a direct de pressive action on the secretory apparatus in GLC8 cells. This latter effect also is mediated by a PTX-sensitive G-protein but, contrary to VOCC inhibition, it can be reversed by elevations of cAMP levels. Thes e results show for the first time that opioids effectively depress bot h Ca2+ influx and Ca2+-dependent hormone release in SCLC cells by usin g multiple modulatory pathways. It can be speculated that the two mech anisms may contribute to the opioid antimitogenic action on lung neuro endocrine carcinoma cells.