Dependence of prolactin release on coupling between Ca2+ mobilization and voltage-gated Ca2+ influx pathways in rat lactotrophs

Two Ca2+-mobilizing receptors expressed in lactotrophs, endothelin-A (ETA) and thyrotropin-releasing hormone (TRH), induce a rapid Ca2+ release from intracellular stores and prolactin (PRL) secretion but differ in their actions during the sustained stimulation; TRH facilitates and ET-1 inhibits voltage-gated calcium influx (VGCI) and PRL secretion. In pertussis toxin (PTX)-treated cells, ET-1-induced inhibition of VGCI was abolished and the pattern of Ca2+ signaling was highly comparable with that observed in TRH-stimulated cells. The addition of Cs+, a relatively specific blocker of inward rectifier K+ channels, mimicked the effect of PTX on the pattern of ET-1-induced sustained Ca2+ signaling, but only in about 50% of cells, and did not affect agonist-induced inhibition of PRL secretion. Extracellular Cs+ was also ineffective in altering the TRH-induced facilitation of VGCI and PRL secretion. Furthermore, apamin and paxilline, specific blockers of Ca2+-activated SK-and BK-type K+ channels, respectively; E-4031, a blocker of ether a-go-go K+ channel; and linopirdine, a blocker of M-type K+ channel, did not affect the agonist-specific patterns of calcium signaling and PRL secretion. These results suggest that ET-1 inhibits VGCI through activation of Cs+-sensitive channels, presumably the Gi/o-controlled inward rectifier K+ channels, and that this agonist also inhibits PRL release, but downstream of Ca2+ influx. Further studies are required to identify the mechanism of sustained TRH-induced facilitation of VGCI and PRL secretion.