Multiple Roles of Gi/o Protein-Coupled Receptors in Control of Action Potential Secretion Coupling in Pituitary Lactotrophs

摘要

Gi/o protein-coupled receptors, signaling through G protein-dependent and -independent pathways, have prominent effects on secretion by modulating calcium signaling and regulating the size of the releasable secretory pool, the rates of exocytosis and endocytosis, and de novo synthesis. Pituitary cells fire action potentials spontaneously, and the associated calcium influx is sufficient to maintain prolactin (PRL) release, but not gonadotropin release, at high and steady levels for many hours. Such secretion, termed intrinsic, spontaneous or basal, reflects fusion of secretory vesicles triggered by the cell type-specific pattern of action potentials. In lactotrophs, activation of endothelin ETA and dopamine D2 receptors causes inhibition of spontaneous electrical activity and basal adenylyl cyclase activity, accompanied with inhibition of basal PRL release. Agonist-induced inhibition of cAMP production and firing of action potentials is abolished in cells with blocked pertussis toxin (PTX)-sensitive Gi/o signaling pathway. However, agonist-induced inhibition of PRL release is only partially relieved in such treated cells, indicating that both receptors also inhibit exocytosis downstream of cAMP/calcium signaling. The PTX-insensitive step in agonist-induced inhibition of PRL release is not affected by inhibition of PI3-kinase and GSK-3, but is partially rescued by down-regulation of the Gzα expression. Thus, ETA and D2 receptors inhibit basal PRL release not only by blocking electrical activity but also by desensitizing calcium-secretion coupling.