Constitutive somatostatin receptor subtype-3 signaling suppresses growth hormone synthesis.

Somatostatin signals through somatostatin receptor subtypes 2 and 5 to attenuate GH secretion. Although expressed in normal pituitary glands and in GH-secreting pituitary tumors, function was unclear, and we have now determined the role of duanyu1942R3 in somatotroph function. Stable rat pituitary tumor cell (GC) transfectants of human duanyu1942R3 showed suppression of rat (r) GH promoter activity, GH mRNA expression, and secreted GH concordant with suppressed cAMP/protein kinase A signaling. In contrast, cAMP levels and GH expression were unchanged in cells expressing a mutant duanyu1942R3 DRY motif GH expression was rescued by treatment of with forskolin and 8-bromo-cAMP. Gpduanyu1942R3(WT) exhibited activation of glycogen synthase kinase3-β (GSK3-β), a substrate, which was also reversed by 8-Bromo-cAMP treatment. Moreover, GH transcriptional inhibition was rescued by inhibition of GSK3-β. Gpduanyu1942R3(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 duanyu1942R3 activity mediates transcriptional repression of GH through leading to subsequent activation of GSK3-β and increased Pit-1 phosphorylation and ultimately attenuating Pit-1 binding to the rGH promoter.

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