CYCLIC CMP PHOSPHODIESTERASE: BIOLOGICAL INVOLVEMENT AND ITS REGULATION BY AGENTS

Abstract

ABSTRACT Occurrence of cyclic CMP phosphodiesterase (C-PDE) was shown recently in a number of mammalian tissues. Levels of C-PDE are generally 2-3 orders of magnitude lower than those of cyclic AMP phosphodiesterase (A-PDE) and cyclic GMP phosphodiesterase (G-PDE). We found that decreased activity levels of C-PDE are invariably associated with tissues undergoing rapid cell proliferation, either physiologic or pathologic, as exemplified by the regenerating liver, the ontogenesis of guinea pig tissues, and the fast-growing Morris hepatoma 3924A. Changes in the activity levels of A-PDE and G-PDE, on the other hand, were variable and tissue-specific, suggesting that catabolism of cyclic CMP may be more critically related to cell proliferation than that of cyclic AMP or cyclic GMP, or both. C-PDE, which requires Fe 2+ or Mg 2+ for its maximal activity and has a Km for cyclic CMP of about 2-6 mM, was partially purified from pig or rat livers to remove most of the contaminating A-PDE and G-PDE. Classical phosphodiesterase inhibitors (such as papaverine) are without effects on C-PDE at concentrations that inhibit A-PDE and G-PDE 70-90%. Imidazole stimulates both A-PDE and G-PDE, but not C-PDE. 2′-Deoxy cyclic AMP (a specific inhibitor of A-PDE) and 2′-deoxy cyclic GMP (a specific inhibitor of G-PDE) are poor and non-specific inhibitors of C-PDE. Potassium phosphate and adenosine phosphates (mono-, di-, tri-, and tetra-), while greatly inhibiting C-PDE and slightly inhibiting G-PDE, conversely stimulate A-PDE. The partially purified C-PDE is activated by mercaptoethanol, and this activated (reduced) enzyme requires Mg 2+ as a metal activator while its activity is now no longer dependent on Fe 2+ . It is suggested that the newly identified C-PDE is a potential site of bioregulation particularly in proliferative processes, and of pharmacological interventions as well.