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Dopamine Inhibits Basal Prolactin Release in Pituitary Lactotrophs through Pertussis Toxin-Sensitive and -Insensitive Signaling Pathways

Arturo E. Gonzalez-Iglesias¹, Takayo Murano¹, Shuo Li, Melanija Tomi and Stanko S. Stojilkovic

Section on Cellular Signaling, Program in Developmental Neuroscience, National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Dr. Stanko Stojilkovic, National Institute of Child Health and Human Development, Building 49, Room 6A-36, 49 Convent Drive, Bethesda, Maryland 20892-4510. E-mail: stankos{at}helix.nih.gov.

Dopamine D2 receptors signal through the pertussis toxin (PTX)-sensitive G_i/o and PTX-insensitive G_z proteins, as well as through a G protein-independent, β-arrestin/glycogen synthase kinase-3-dependent pathway. Activation of these receptors in pituitary lactotrophs leads to inhibition of prolactin (PRL) release. It has been suggested that this inhibition occurs through the G_i/o- protein-mediated inhibition of cAMP production and/or G_i/o-β dimer-mediated activation of inward rectifier K⁺ channels and inhibition of voltage-gated Ca²⁺ channels. Here we show that the dopamine agonist-induced inhibition of spontaneous Ca²⁺ influx and release of prestored PRL was preserved when cAMP levels were elevated by forskolin treatment. We further observed that dopamine agonists inhibited both spontaneous and depolarization-induced Ca²⁺ influx in untreated but not in PTX-treated cells. This inhibition was also observed in cells with blocked inward rectifier K⁺ channels, suggesting that the dopamine effect on voltage-gated Ca²⁺ channel gating is sufficient to inhibit spontaneous Ca²⁺ influx. However, agonist-induced inhibition of PRL release was only partially relieved in PTX-treated cells, indicating that dopamine receptors also inhibit exocytosis downstream of voltage-gated Ca²⁺ influx. The PTX-insensitive step in agonist-induced inhibition of PRL release was not affected by the addition of wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and lithium, an inhibitor of glycogen synthase kinase-3, but was attenuated in the presence of phorbol 12-myristate 13-acetate, which inhibits G_z signaling pathway in a protein kinase C-dependent manner. Thus, dopamine inhibits basal PRL release by blocking voltage-gated Ca²⁺ influx through the PTX-sensitive signaling pathway and by desensitizing Ca²⁺ secretion coupling through the PTX-insensitive and protein kinase C-sensitive signaling pathway.