CYCLIC GMP PHOSPHODIESTERASES IN PC12 DIFFERENTIATION

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DESCRIPTION NGF causes a rapid loss of cGMP-stimulated cyclic nucleotide phosphodiesterase (PDE2) activity in PC12 cells (50% reduction after 24 hours). Longer treatment with NGF results in a greater than 80% reduction in PDE 2 activity. PDE2 mRNA is not rapidly decreased but CaM-stimulated PDE (PDE1) mRNAs are induced by NGF-differentiation. NGF action to promote neuronal survival or PC12 differentiation is hypothesized to have effects on transcription levels and on post - translational modification of distinct PDEs, and proteins regulating them, to decrease the overall PDE activity of the cell. Sympathetic differentiation is further hypothesized to shift cyclic nucleotide metabolism from a cyclic GMP-regulated to a calcium-regulated state. The specific aims of the study are 1) structural characterization of PDE1 and PDE2 cDNAs from PC12 and sympathetic neurons 2) assessment of NGF effects on PC12 and rat sympathetic ganglia PDE mRNAs and proteins and 3) identification of PDE1- and PDE2-interacting proteins through molecular cloning and immunochemical analysis.