Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase.

The brain as well as other mammalian tissues contains several different forms of cyclic nucleotide phosphodiesterase separable by polyacrylamide gel electrophoresis. Each tissue and each individual type of cell has its own distinctive pattern and ratio of these multiple forms of phosphodiesterase. The different forms have several distinguishing properties and characteristics, and their activities may be differentially regulated both acutely and chronically. The enzyme forms have different stabilities, kinetic properties, substrate specificities, and sensitivities to an endogenous activator and to several inhibitors of phosphodiesterase. The phosphodiesterase inhibitors studied not only inhibit the different forms of phosphodiesterase to different degrees but apparently do so by different mechanisms. Thus whereas theophylline, cyclic GMP, and low concentrations of papaverine inhibit the phosphodiesterases by competing with the substrate (cyclic AMP), trifluoperazine apparently inhibits phosphodiesterase by interfering with the phosphodiesterase activator. This confers a great deal of specificity to this drug, since only one form of phosphodiesterase is markedly activated by the activator. Chronically, a specific form of phosphodiesterase appears to be inducible. This induction is probably controlled by the intracellular cyclic AMP concentration. The phosphodiesterase activator also appears to be regulatable, the age of the animal being one of the factors controlling its activity. Finally, since different types of cells have different relative amounts of the phosphodiesterases and since these forms of the enzyme can be differentially inhibited by drugs, it may be possible to develop drugs which will selectively increase the cyclic AMP concentration in discrete cell types. Evidence that cyclic AMP is involved in certain disease states suggests further that by selectively altering the concentration of cyclic AMP in these cells, one might be able to alter the course of the disease.