Relevant cAMP-specific phosphodiesterase isoforms in human pituitary: Effect of Gs alpha mutations

Both cAMP production by adenylyl cyclase and cAMP degradation by phosphodie sterases account for intracellular cAMP levels. We previously demonstrated an increased phosphodiesterase activity in GH-secreting adenomas bearing th e gsp oncogene. Here we characterize both the activity and the expression o f cAMP-specific phosphodiesterase genes in the human pituitary and in gsp and gsp - GH-secreting adenomas and analyze the impact of this intracellul ar feedback mechanism on the levels of cAMP-responsive element-binding prot ein phosphorylation. Normal pituitary and gsp- GH-secreting adenomas showed similar phosphodiesterase activities, and 7-fold higher levels were observ ed in gsp+ tumors. In these tumors the increased activity was mainly owing to isobutyl-methyl-xanthine-sensitive phosphodiesterase 4 and to isobutyl-m ethyl-xanthine-insensitive isoforms. By semiquantitative RT-PCR, all phosph odiesterase 4 transcripts were expressed in the normal and tumoral pituitar y. However, the levels of phosphodiesterase 4C and 4D messenger RNAs were s ignificantly higher in gsp+ than in gsp- GH- secreting adenomas and normal pituitary. Expression of the thyroid-specific isobutyl-methyl-xanthine-inse nsitive phosphodiesterase 8B was absent in the normal pituitary but detecta ble in almost all GH-secreting adenomas and higher in gsp + (P < 0.02). The refore, this study provides a characterization of phosphodiesterase express ion in human pituitary and demonstrates a dramatic induction of the cAMP-sp ecific phosphodiesterases 4C and phosphodiesterases 4D and phosphodiesteras es 8B in gsp+ GH-secreting adenomas. Similar levels of cAMP-responsive elem ent-binding protein phosphorylation were observed in gsp - and gsp + GH-sec reting adenomas; however, phosphodiesterase blockade caused an increase in cAMP-responsive element-binding protein phosphorylation that was significan tly higher in gsp+ than in gsp- adenomas. Because cAMP-responsive element-b inding protein represents the principal end point of the cAMP pathway, thes e results suggest that the enhanced phosphodiesterase activity may have a s ignificant impact on the phenotypic expression of gsp mutations.