@article {Tomi{\'c}1329, author = {Melanija Tomi{\'c} and Fredrick Van Goor and Mu-Lan He and Dragoslava Zivadinovic and Stanko S. Stojilkovic}, title = {Ca2+-Mobilizing Endothelin-A Receptors Inhibit Voltage-Gated Ca2+ Influx through Gi/oSignaling Pathway in Pituitary Lactotrophs}, volume = {61}, number = {6}, pages = {1329--1339}, year = {2002}, doi = {10.1124/mol.61.6.1329}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textendash}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{\textendash}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{\textendash}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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/61/6/1329}, eprint = {https://molpharm.aspetjournals.org/content/61/6/1329.full.pdf}, journal = {Molecular Pharmacology} }