Activation of delta-opioid receptors inhibits neuronal-like calcium channels and distal steps of Ca(2+)-dependent secretion in human small-cell lung carcinoma cells.
Human small-cell lung carcinoma (SCLC) cells express neuronal-like voltage-operated calcium channels (VOCCs) and release mitogenic hormones such as serotonin (5-HT). Opioid peptides, on the other hand, have been shown to reduce SCLC cell proliferation by an effective autocrine pathway. Here we show that in GLC8 SCLC cells, only delta-opioid receptor subtype mRNA is expressed. Consistently, the selective delta-opioid agonist [D-Pen2-Pen5]-enkephalin (DPDPE), but not mu and kappa agonists, potently and dose-dependently inhibits high-threshold (HVA) VOCCs in these cells. As in peripheral neurons, this modulation is largely voltage-dependent, mediated by pertussis toxin (PTX)-sensitive G-proteins, cAMP-independent, and mainly affecting N-type VOCCs. With the same potency and selectivity, DPDPE also antagonizes the Ca(2+)-dependent release of [3H]serotonin ([3H]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 suggests that besides inhibiting HVA VOCCs, opioids also exert a direct depressive 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. These results show for the first time that opioids effectively depress both Ca2+ influx and Ca(2+)-dependent hormone release in SCLC cells by using multiple modulatory pathways. It can be speculated that the two mechanisms may contribute to the opioid antimitogenic action on lung neuroendocrine carcinoma cells.
Sher
E
E
Department of Medical Pharmacology, University of Milan, Italy.
Cesare
P
P
Codignola
A
A
Clementi
F
F
Tarroni
P
P
Pollo
A
A
Magnelli
V
V
Carbone
E
E
D000700:Analgesics / Q000494:pharmacology; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D000242:Cyclic AMP / Q000502:physiology; D004594:Electrophysiology; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008175:Lung Neoplasms; D008564:Membrane Potentials / Q000187:drug effects; D008969:Molecular Sequence Data; D018847:Opioid Peptides / Q000494:pharmacology; D037342:Pertussis Toxin; D011189:Potassium Chloride / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000096:biosynthesis / Q000187:drug effects; D012701:Serotonin / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology; D019284:Thapsigargin; D014316:Tritium / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D000700:Analgesics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004745:Enkephalins; D004791:Enzyme Inhibitors; D007476:Ionophores; D018847:Opioid Peptides; D017465:Receptors, Opioid, delta; D013729:Terpenes; D010566:Virulence Factors, Bordetella; D014316:Tritium; D012701:Serotonin; D015759:Ionomycin; D011189:Potassium Chloride; D019284:Thapsigargin; D020881:Enkephalin, D-Penicillamine (2,5)-; D000242:Cyclic AMP; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D002118:Calcium