Modes of inhibition by acylcarnitines, adriamycin and trifluoperazine of cardiac phospholipid-sensitive calcium-dependent protein kinase.
Palmitoylcarnitine, adriamycin, and trifluoperazine competively inhibited, with respect to phosphatidylserine (a phospholipid cofactor), purified cardiac phospholipid-sensitive Ca2+-dependent protein kinase, with apparent Ki values of 3, 49 and 14 microM respectively. These compounds also inhibited the enzyme competitively with respect to Ca2+ (a metal activator), with corresponding apparent Ki values of 0.8, 140 and 9 microM. A synergistic inhibition was observed when palmitoylcarnitine and trifluoperazine were present in combination. A simple addition inhibition on the other hand, was observed for the combination of either palmitoylcarnitine and adriamycin, or trifluoperazine and adriamycin. 1,3-Diolein decreased the inhibitory effect of trifluoperazine by increasing the affinity of the enzyme for phosphatidylserine. The results indicate that the recently identified phospholipid-sensitive species of Ca2+-dependent protein kinase was inhibited by a variety of agents, probably via their abilities to interfere with a hydrophobic interaction between phospholipid and the enzyme, an interaction presumably required to confer upon the enzyme a Ca2+ sensitivity. Because other long-chain fatty acylcarnitines (stearoyl- and linoleoylcarnitine), short-chain fatty acylcarnitines (such as octanoylcarnitine) and palmitoyl CoA, compared to palmitoylcarnitine, were less active as inhibitors, it is further suggested that lipophilicity as well as other structural determinants are crucial for the ability of compounds to regulate the enzyme activity.
D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000494:pharmacology; D002331:Carnitine / Q000031:analogs & derivatives*; D002417:Cattle; D004075:Diglycerides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D009206:Myocardium / Q000201:enzymology*; D010172:Palmitoylcarnitine / Q000494:pharmacology*; D010743:Phospholipids / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D014268:Trifluoperazine / Q000494:pharmacology*
D004075:Diglycerides; D010743:Phospholipids; D047428:Protein Kinase Inhibitors; D010172:Palmitoylcarnitine; D014268:Trifluoperazine; D004317:Doxorubicin; D002331:Carnitine; D002118:Calcium; C013965:diolein