title: Constitutive somatostatin receptor subtype-3 signaling suppresses growth hormone synthesis.
abstract: Somatostatin signals through somatostatin receptor subtypes (SSTR) 2 and 5 to attenuate GH secretion. Although expressed in normal pituitary glands and in GH-secreting pituitary tumors, SSTR3 function was unclear, and we have now determined the role of SSTR3 in somatotroph function. Stable rat pituitary tumor cell (GC) transfectants of human SSTR3 (GpSSTR3(WT)) showed suppression of rat (r) GH promoter activity, GH mRNA expression, and secreted GH concordant with suppressed cAMP/protein kinase A (PKA) signaling. In contrast, cAMP levels and GH expression were unchanged in cells expressing a mutant SSTR3 DRY motif (GpSSTR3(R141A)). GH expression was rescued by treatment of GpSSTR3(WT) with forskolin and 8-bromo-cAMP. GpSSTR3(WT) exhibited activation of glycogen synthase kinase3-β (GSK3-β), a PKA substrate, which was also reversed by 8-Bromo-cAMP treatment. Moreover, SSTR3-dependent GH transcriptional inhibition was rescued by inhibition of GSK3-β. GpSSTR3(WT) exhibited elevated Pit-1 serine phosphorylation and decreased Pit-1 occupancy of the rGH promoter with sustained Pit-1 expression. GSK3-β and Pit-1 physically interacted with each other, indicating that Pit-1 may be a GSK3-β phosphorylation substrate. In conclusion, constitutive SSTR3 activity mediates transcriptional repression of GH through cAMP/PKA, leading to subsequent activation of GSK3-β and increased Pit-1 phosphorylation and ultimately attenuating Pit-1 binding to the rGH promoter.
authors.affiliation: Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048.
authors.forename: Tamar
authors.initials: T
authors.lastname: Eigler
authors.forename: Anat
authors.initials: A
authors.lastname: Ben-Shlomo
authors.forename: Cuiqi
authors.initials: C
authors.lastname: Zhou
authors.forename: Ramtin
authors.initials: R
authors.lastname: Khalafi
authors.forename: Song-Guang
authors.initials: SG
authors.lastname: Ren
authors.forename: Shlomo
authors.initials: S
authors.lastname: Melmed
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D051381:Rats; D017481:Receptors, Somatostatin / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D017481:Receptors, Somatostatin; C103631:somatostatin receptor 3; D013006:Growth Hormone; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3