EVIDENCE THAT PITUITARY ADENYLATE-CYCLASE ACTIVATING POLYPEPTIDE SUPPRESSES FOLLICLE-STIMULATING HORMONE-BETA MESSENGER-RIBONUCLEIC-ACID LEVELS BY STIMULATING FOLLISTATIN GENE-TRANSCRIPTION

There is accumulating evidence to suggest that pituitary adenylate cyc lase-activating polypeptide (PACAP) may be an important modulator of g onadotrope function. One of the actions of PACAP identified previously is to decrease FSH beta messenger RNA (mRNA) levels. In the present s eries of experiments we demonstrate that PACAP-induced suppression of FSH beta mRNA correlates with a rise in follistatin mRNA levels in pri mary pituitary cell cultures. Transient transfection of gonadotrope-de rived alpha T3-1 cells with a rat follistatin promoter-luciferase repo rter plasmid reveals that PACAP stimulates follistatin gene transcript ion. PACAP stimulation of LUC activity was maximal at concentrations a s low at 1 nM. Furthermore, in alpha T3-1 cells PACAP activation of th e follistatin promoter appears to be via the cAMP-dependent protein ki nase A pathway. Accordingly, we propose that PACAP stimulates follista tin transcription, which neutralizes activin activity and thereby redu ces FSH beta mRNA. Since PACAP and follistatin are colocalized in mult iple tissues including the brain, adrenals, and gonads, our findings m ay reflect a broadly distributed autocrine/paracrine mechanism for mod ification of activin effects that is under PACAP control.