The effect of tumor promoters on electrical coupling between human FL cells was investigated with a microelectrode technique. When a low concentration (100 ng/ml) of 12-O-tetradecanoylphorbol 13-acetate (TPA) was added to culture medium, only 6% of the cells showed electrical coupling after 5 hr, whereas in control medium more than 90% of the cells were coupled. In the presence of TPA, cell coupling remained suppressed for at least another 19 hr. When TPA was washed out from the culture medium, the cells commenced electrical coupling: 90% of the cells were coupled within 4 hr of the removal of TPA, a rate very similar to that of nontreated control cells. Therefore, TPA-mediated inhibition of cell coupling is reversible. When TPA was added to a culture in which more than 90% of the cells had already established electrical coupling, the percentage of coupled cells decreased to 6% within 8 hr, indicating that TPA can also diminish already established cell coupling. Inhibition of cell coupling also was achieved with other mouse skin tumor promoters--phorbol 12,13-didecanoate, ingenol dibenzoate, and mezerein--whereas nonpromoting derivatives--phorbol and 4 alpha-phorbol 12,13-didecanoate-showed no effect. None of these compounds changed the membrane potential, membrane resistance, or growth rate of FL cells. Thus, it appears that TPA and structurally-related tumor promoters specifically disturb the formation or function, or both, of cell-cell junctions, without significantly affecting the general properties of the surface membrane or the growth of FL cells.