Synergy between phorbol esters and retinoic acid in inducing protein kinase C activation

All-trans retinoic acid (RA) activates brain protein kinase C (PKC) in a unique fashion. Co-factors such as Ca2+ or PtdSer are not required for histone phosphorylation. Binding experiments have provided evidence that RA does not act as a phorbol-ester-like activator. However, phorbol esters synergistically enhance this activation in a dose-dependent manner and increase the reaction rate up to five-fold when combined with 10 microM RA. Phospholipid-interacting drugs such as phenothiazines and 1-N-(6 aminohexyl) 5-chloro-1-naphthalene-sulfonamide (W7), which compete with PtdSer and inhibit phorbol ester/PtdSer-mediated activation, have potentiating effects on the RA-mediated reaction. RA elicits Ca(2+)-dependent PKC autophosphorylation. The activation resulting from the combined treatment with PtdSer and RA is more than additive in the presence of Ca2+, indicating that PtdSer- and RA-binding sites are distinct. RA shares several characteristics of activation with sodium deoxycholate and arachidonic acid. These present results suggest that the direct activation of PKC may have physiological and/or pharmacological relevance in the signaling triggered by retinoids.