INDUCTION OF CYCLIC-AMP AND CYCLIC-GMP 3' 5'-CYCLIC NUCLEOTIDE PHOSPHODIESTERASE ACTIVITIES IN NEUROBLASTOMA LINES UNDER DIFFERENTIATING CONDITIONS/

It is now widely accepted that cyclic nucleotide phosphodiesterases (P DEs) play fundamental roles in signal transduction pathways; they show a remarkable molecular complexity, different tissue distribution and complex regulatory mechanisms. Here we report PDE isoforms expression in two dibutyryl cyclic AMP differentiated murine cell lines: the hybr id neuroblastoma-glioma 108CC15 and the parental neuroblastoma N18TG2. They differ in the ability to establish functional synapses, a featur e present only in the former. Ionic exchange chromatography elution pr ofiles of N18TG2 and 108CC15 undifferentiated cell extracts show two m ain peaks of activity. The first one hydrolyzes cyclic GMP and is spec ifically inhibited by Zaprinast, thus representing a member of the PDE S family. The second peak hydrolyzes cyclic AMP and is significantly i nhibited by rolipram, as all the PDE4 family members. The induction of differentiation by dibutyryl cyclic AMP in both clonal lines results in an increase of PDE activities only after 3 hr of treatment, suggest ing that protein neosynthesis is involved. Interestingly in both clone s, besides the increase in cyclic AMP hydrolyzing specific activity (3 .1-fold in 108CC15 and 2.5-fold in N18TG2), we also observed an increa se in cyclic GMP hydrolyzing activity (1.7-fold in 108CC15 and 4.3-fol d in N18TG2). While the induction of PDE4, previously reported also in other cellular systems, could be considered as a feedback response to the higher cyclic AMP levels, this is not true for the isoform that h ydrolyzes cyclic GMP. These data suggest that the induction of PDE iso forms in neuroblastoma cells could be related to the activation of neu ronal differentiative pathway. (C) 1997 ISDN.