Multiple roles of Gi/o protein-coupled receptors in control of action potential secretion coupling in pituitary lactotrophs.
G(i/o) protein-coupled receptors, signaling through G protein-dependent and protein-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 ET(A) and dopamine D(2) 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 G(i/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 phosphoinositide 3-kinase and glycogen synthase kinase-3 but is partially rescued by downregulation of the G(z)alpha expression. Thus, ET(A) and D(2) receptors inhibit basal PRL release not only by blocking electrical activity but also by desensitizing calcium-secretion coupling.
Stojilkovic
Stanko S
SS
Section on Cellular Signaling, Program in Developmental Neuroscience, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510, USA. stankos@helix.nih.gov
Murano
Takayo
T
Gonzalez-Iglesias
Arturo E
AE
Andric
Silvana A
SA
Popovic
Marko A
MA
Van Goor
Fredrick
F
Tomić
Melanija
M
D000818:Animals; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D006801:Humans; D052682:Lactotrophs / Q000378:metabolism*; D011388:Prolactin / Q000378:metabolism; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction
D043562:Receptors, G-Protein-Coupled; D011388:Prolactin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go