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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 δ-opioid receptor subtype mRNA is expressed. Consistently, the selective δ-opioid agonist [d-Pen2-Pen5]-enkephalin (DPDPE), but not μ and κ 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 Ca2+-dependent release of [3H]serotonin ([3H]5-HT) from GLC8 cells. However, DPDPE inhibits not only the depolarization-induced release, but also the Ca2+-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 Ca2+-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.

the journal of neuroscience/the journal of neuroscience

Activation of δ-Opioid Receptors Inhibits Neuronal-Like Calcium Channels and Distal Steps of Ca<sup>2+</sup>-Dependent Secretion in Human Small-Cell Lung Carcinoma Cells

Activation of δ-Opioid Receptors Inhibits Neuronal-Like Calcium Channels and Distal Steps of Ca2+-Dependent Secretion in Human Small-Cell Lung Carcinoma Cells

Activation of δ-Opioid Receptors Inhibits Neuronal-Like Calcium Channels and Distal Steps of Ca²⁺-Dependent Secretion in Human Small-Cell Lung Carcinoma Cells