Studies on the mechanism of phorbol ester-induced inhibition of intercellular junctional communication.
Intercellular gap-junctional communication was measured using [14C]citrulline incorporation in co-cultures of argininosuccinate lyase-deficient human fibroblasts and argininosuccinate synthetase-deficient Chinese Hamster V79 cells. As previously shown, in this system junctional communication is completely inhibited by the tumor promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). In the absence of extracellular calcium, TPA inhibition was less pronounced. However, synergism with calcium ionophore A23187 could not be demonstrated. Chlorpromazine, trifluoperazine and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester partially antagonised the effect of TPA. No antagonism was demonstrable between calmidazolium and TPA. Treatment of co-cultures with exogenous phospholipase C or 1-oleoyl-2-acetylglycerol (OAG) resulted in communication inhibition, suggesting that protein kinase C activation is involved in the mechanism of phorbol ester-mediated communication inhibition. However co-cultures which had been made refractory to TPA by prolonged exposure to high concentrations remained sensitive to inhibition by phospholipase C and OAG. These results suggest either that diacylglycerol can produce other effects independent of protein kinase C activation, or that refractoriness to phorbol esters is not simply due to a decrease in the amount of protein kinase C.
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects*; D002478:Cells, Cultured; D002746:Chlorpromazine / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004075:Diglycerides / Q000494:pharmacology; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D010704:Phorbols / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000494:pharmacology
D004075:Diglycerides; D007093:Imidazoles; D010704:Phorbols; D000001:Calcimycin; C031938:calmidazolium; C006014:8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate; D005707:Gallic Acid; C038237:1-oleoyl-2-acetylglycerol; D010738:Type C Phospholipases; D013755:Tetradecanoylphorbol Acetate; D002746:Chlorpromazine