This work extends the study of the mechanism of phosphodiesterase regulation by an endogenous protein activator. The activator stored in the cell membrane fraction can be released into the cytosol by a cAMP-dependent phosphorylation of a membrane binding site. A subcellular distribution of the localization of activator in rat brain and its release has been performed. The activator is located mainly in the mitochondrial fraction and particularly in the mitochondrial subfractions containing synaptic membranes and synaptic vesicles. Nearly 100% of the activator in these fractions can be released by the cAMP-dependent phosphorylation. The mechanism for cAMP during periods of sustained synaptic transmission and could explain post-synaptic receptor supersensitivity to neurotransmitters. BIBLIOGRAPHIC REFERENCES: Gnegy, M.E., Nathanson, J.A. and Uzunov, P.: Release of the phosphodiesterase activator by cyclic AMP-dependent ATP: Protein phosphodiesterase from subcellular fractions of rat brain. Biochim. Biophys. Acta 497: 75-85, 1977. Costa, E., Gnegy, M.E. and Uzunov, P.: Regulation of dopamine receptor sensitivity by an endogenous protein activator or adenylate cyclase. Naunyn-Schmied. Arch. Pharmacol. 297: S47-S48, 1977.