An enhancement of the cellular cAMP level has been shown to protect against phorbol ester-induced inhibition of gap junctional intercellular communication (GJIC) and induction of morphological transformation in Syrian hamster embryo (SHE) cells. Cholera toxin, forskolin, 3-isobutyl-1-methylxanthine (IBMX) and theophylline counteracted the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inhibition of GJIC. The enhancement of communication by these compounds was independent of the TPA concentration, as well as whether the cells were treated with TPA prior to or after the cAMP elevating agents. The induced increase in the cAMP level by cholera toxin occurred in the same concentration range as the enhancement of GJIC. With forskolin the effect on GJIC was apparent at concentrations 10 times lower than needed to enhance the cAMP level. IBMX and theophylline were found to enhance GJIC with only a 20% elevation of cAMP. The cAMP elevating compounds also suppressed the response of TPA on induction of transformed morphology in SHE cells.