PT - JOURNAL ARTICLE AU - Melanija Tomić AU - Fredrick Van Goor AU - Mu-Lan He AU - Dragoslava Zivadinovic AU - Stanko S. Stojilkovic TI - Ca<sup>2+</sup>-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca<sup>2+</sup> Influx through G<sub>i/o</sub>Signaling Pathway in Pituitary Lactotrophs AID - 10.1124/mol.61.6.1329 DP - 2002 Jun 01 TA - Molecular Pharmacology PG - 1329--1339 VI - 61 IP - 6 4099 - http://molpharm.aspetjournals.org/content/61/6/1329.short 4100 - http://molpharm.aspetjournals.org/content/61/6/1329.full SO - Mol Pharmacol2002 Jun 01; 61 AB - In excitable cells, receptor-induced Ca2+ release from intracellular stores is usually accompanied by sustained depolarization of cells and facilitated voltage-gated Ca2+ influx (VGCI). In quiescent pituitary lactotrophs, however, endothelin-1 (ET-1) induced rapid Ca2+ release without triggering Ca2+ influx. Furthermore, in spontaneously firing and depolarized lactotrophs, the Ca2+-mobilizing action of ET-1 was followed by inhibition of spontaneous VGCI caused by prolonged cell hyperpolarization and abolition of action potential-driven Ca2+ influx. Agonist-induced depolarization of cells and enhancement of VGCI upon Ca2+ mobilization was established in both quiescent and firing lactotrophs treated overnight with pertussis toxin (PTX). Activation of adenylyl cyclase by forskolin and addition of cell-permeable 8-bromo-cAMP did not affect ET-1–induced sustained inhibition of VGCI, suggesting that the cAMP-protein kinase A signaling pathway does not mediate the inhibitory action of ET-1 on VGCI. Consistent with the role of PTX-sensitive K+ channels in ET-1–induced hyperpolarization of control cells, but not PTX-treated cells, ET-1 decreased the cell input resistance and activated a 5 mM Cs+-sensitive K+ current. In the presence of Cs+, ET-1 stimulated VGCI in a manner comparable with that observed in PTX-treated cells, whereas E-4031, a specific blocker of ether-a-go-go–related gene-like K+ channels, was ineffective. Similar effects of PTX and Cs+ were also observed in GH3 immortalized cells transiently expressing ETA receptors. These results indicate that signaling of ETA receptors through the Gi/o pathway in lactotrophs and the subsequent activation of inward rectifier K+ channels provide an effective and adenylyl cyclase-independent mechanism for a prolonged uncoupling of Ca2+ mobilization and influx pathways.