We had previously described a unique 87 kilodalton protein of which the phosphorylation was inhibited by calcium binding proteins, S-100 and calmodulin. Further evidence was obtained to establish that this protein represented a major substrate of calcium/phospholipid dependent protein kinase (protein kinase C). The mechanisms of inhibition of the 87k protein by S-100 and calmodulin was addressed. Effects of various neuropeptides on the phosphorylation of synaptic membrane proteins was investigated. It was found that calcitonin and somatostatin are potent inhibitors of protein phosphorylation. Detailed characterization of this effect of these neuropeptides was performed. The involvement of protein kinase C in the modulation of receptor sensitivity was further investigated using human choriogonadotropin (hCG) sensitive adenylate cyclase in cultured leydig cells as a model system. The effect of chronic treatment of rats with lithium on the CNS protein phosphorylation system was investigated. Lithium treatment was found to produce a marked increase in the phosphorylation of a 64 kilodalton protein.