PITUITARY ADENYL CYCLASE-ACTIVATING PEPTIDE - A HYPOPHYSIOTROPIC FACTOR THAT STIMULATES PROOPIOMELANOCORTIN GENE-TRANSCRIPTION, AND PROOPIOMELANOCORTIN-DERIVED PEPTIDE SECRETION IN CORTICOTROPIC CELLS

The biological effects of pituitary adenylate cyclase-activating pepti de (PACAP) 27 and 38 on peptide secretion and gene regulation were stu died in the mouse corticotrope-derived cell line AtT20. Treatment of t hese cells with PACAP 27/38 led to a dose-dependent increase in cAMP c ontent and ACTH accumulation in the medium with an apparent ED(50) val ue close to 10(-9) M. The genomic effects of PACAP were first investig ated by using a reporter gene containing a cAMP responsive element (CR E: TGACGTCA). PACAP 27/38 stimulate transcription from this construct and the effect is further increased when cells are cotreated with the phosphodiesterase inhibitor rolipram. Furthermore, we show by measurin g nuclear heterologous proopiomelanocortin (POMC) RNA levels or by usi ng a reporter gene containing the POMC promoter region, that PACAP sti mulates POMC transcription. This transcriptional stimulation is mediat ed by the cAMP-dependent protein kinase (PKA) since genetic inactivati on of PKA by a dominant inhibitory mutant of this enzyme completely ab olished the effect of PACAP on POMC transcription. Finally, we show th at the transcriptional stimulation of POMC by PACAP is repressed by th e glucocorticoid receptor agonist dexamethasone. Taken together, these data suggest that PACAP is a hypophysiotropic hormone that exert simi lar if not identical functions as corticotropin-releasing hormone (CRH ) on corticotrope cells.