Mori T, Takai Y, Minakuchi R, Yu B, Nishizuka Y
J Biol Chem. 1980 Sep 25;255(18):8378-80.
Ca2+-activated, phospholipid-dependent protein kinase recently found in mammalian tissues (Takai, Y., Kishimoto, A., Iwasa, Y., Kawahara, Y., Mori, T., and Nishizuka, Y. (1979) J. Biol. Chem. 254, 3692-3695) is inhibited by various phospholipid-interacting drugs such as chlorpromazine, imipramine, phentolamine, dibucaine, verapamil, and tetracaine. This effect is attributed to the inhibition of the activation process but not to the interaction with the active site of enzyme. This is supported by the fact that a catalytic fragment of this enzyme, which is obtained by limited proteolysis with Ca2+-dependent neutral protease, is fully active without without Ca2+ and phospholipid and is not susceptible to any of these drugs. Kinetic analysis suggests that these drugs cause such inhibition competitively with phospholipid. None of these drugs appears to compete with Ca2+ or to counteract the unique effect of unsaturated diacylglycerol. Unsaturated diacylglycerol has been shown previously to increase markedly the affinity of enzyme for Ca2+ as well as for phospholipid and thereby serve as an initiator for the activation of this protein kinase. Neither cyclic AMP-dependent nor cyclic GMP-dependent protein kinase is susceptible to these phospholipid-interacting drugs.
最近在哺乳动物组织中发现的钙激活的、磷脂依赖性蛋白激酶（高井洋、岸本明、岩佐洋、川原洋、森田、西冢泰（1979年）《生物化学杂志》254卷，3692 - 3695页）受到多种磷脂相互作用药物的抑制，如氯丙嗪、丙咪嗪、酚妥拉明、丁卡因、维拉帕米和丁哌卡因。这种作用归因于对激活过程的抑制，而非与酶的活性位点相互作用。这一观点得到以下事实的支持：该酶经钙依赖性中性蛋白酶有限水解获得的催化片段，在无钙和磷脂的情况下仍具有完全活性，且对这些药物均不敏感。动力学分析表明，这些药物与磷脂竞争性地导致这种抑制作用。这些药物似乎均不与钙竞争，也不抵消不饱和二酰甘油的独特作用。先前已表明，不饱和二酰甘油可显著增加该酶对钙以及磷脂的亲和力，从而作为这种蛋白激酶激活的启动剂。环磷酸腺苷依赖性蛋白激酶和环磷酸鸟苷依赖性蛋白激酶均对这些磷脂相互作用药物不敏感。
