Abstract Protein kinase C was activated in Xenopus laevis oocytes by phorbol ester treatment and its effects on the inositol trisphosphate/Ca(2+) transmembrane signalling pathway analysed. Induction of the pathway was achieved by ligand stimulation of TRH receptors translated from GH(3) pituitary cell mRNA. In voltage-clamped oocytes bath application of peptide, injection of guanosine 5'-(3-O-thio) triphosphate (GTPgammaS), inositol trisphosphate or Ca(2+) all elicited inward membrane currents. Treatment of oocytes with tumour-promoting phorbol esters for 35 min almost completely abolished the ligand and GTPgammaS-induced responses. In contrast, phorbol ester treatment enhanced inositol trisphosphate-generated membrane currents. Ca(2+)-mediated responses remained unaffected by tumour promoters. The data indicate a dual role for protein kinase C in the modulation of transmembrane signalling: a feedback mechanism prevents phosphoinositide turnover whereas a feedforward reaction triggers the effect of intracellular inositol trisphosphate on the Ca(2+) release.