The role of protein kinase C in melanosome dispersion was examined using the melanophores of the lizard Anolis carolinensis and an in-vitro rate method of bioassay. The phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), which directly activates protein kinase C, was able to potentiate the melanophore response to α-MSH in a dose-dependent manner. Similarly, the stimulatory response to forskolin, which activates the adenylate cyclase catalytic subunit, was also potentiated by TPA. The response of the melanophore to cyclic AMP, however, remained unaltered by any dose of TPA. We thus propose that the potentiation of α-MSH potency by TPA is through an interaction of protein kinase C with adenylate cyclase and, more specifically, that this interaction may be at the level of the linkage of the nucleotide regulatory subunit Ns with the catalytic moiety C of adenylate cyclase.