Recent studies are described concerning the physiological role and tissue distribution of Protein I, a synapse-specific phosphoprotein. This protein is present in both the central and the peripheral nervous system and appears to be enriched in synaptic vesicles. It is a major substrate for both Ca2(-)- and cyclic AMP-dependent phosphorylation in the brain. In slices of the facial motor nucleus from rat brainstem, serotonin (5-HT) added to the incubation medium stimulates the phosphorylation of Protein I. This effect is potentiated by low concentrations of isobutylmethylxanthine and is prevented by the serotonin antagonist mianserin.