Huang K P, Huang F L
Section on Metabolic Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892.
Neurochem Int. 1993 May;22(5):417-33. doi: 10.1016/0197-0186(93)90037-6.
Protein kinase C (PKC) enzyme family consists of the Ca(2+)-dependent and -independent subgroups of phospholipid/diacylglycerol (DAG)-stimulated serine/threonine protein kinases. These enzymes exhibit distinct cellular and subcellular localizations in CNS and subtle differences in their biochemical characteristics and substrate specificities. It is believed that each of these isoenzymes respond differently to different input signals. However, detailed mechanism for the functioning of these enzymes in vivo is largely unknown; this is in part due to the absence of specific activator, inhibitor, or substrate for each of these enzymes. Recent advances in biochemical, biophysical, and molecular characterizations have defined certain structural features important to confer the stimulatory responses of these enzymes to Ca2+, DAG or phorbol ester, and Zn2+; other features important for the binding of anionic phospholipids, Ca2+/phospholipid complexes, and cis-unsaturated fatty acids have not yet been characterized. Activation of PKC requires the increase in [Ca2+]i and DAG and/or cis-unsaturated fatty acids. Ca2+ promotes the interactions of the Ca(2+)-dependent subgroup of PKCs with membrane phosphatidylserine (PS) and the enzymes become partially active when simultaneously associated with phosphatidylinositol 4,5-bisphosphate or fully active when DAG is available. Free fatty acids such as arachidonic acid, generated by the activation of phospholipase A2, could synergize with DAG to activate the enzyme maximally. The Ca(2+)-independent subgroup of PKCs also become active when associated with PS at elevated level of DAG. Sustained activation of PKCs leads to the conversion of these enzymes into membrane-inserted and membrane protein-associated forms, which may be responsible for certain long-term neural responses. Activation of PKC results in the phosphorylation of cellular proteins; among them, several calmodulin (CaM)-binding proteins are the prominent substrates of these kinases. Phosphorylation of these proteins by PKC favors the release of CaM, which is required for the Ca2+/CaM-dependent enzymes. Thus, activation of PKCs can lead to diverse cellular responses through such amplification steps. Future studies should be directed at the elucidation of the activation of each PKC isoform in vivo to correlate with the physiological responses.
蛋白激酶C（PKC）酶家族由磷脂/二酰甘油（DAG）刺激的丝氨酸/苏氨酸蛋白激酶的钙依赖性和非依赖性亚组组成。这些酶在中枢神经系统中表现出不同的细胞和亚细胞定位，并且在其生化特性和底物特异性方面存在细微差异。据信这些同工酶中的每一种对不同的输入信号有不同的反应。然而，这些酶在体内发挥作用的详细机制在很大程度上尚不清楚；部分原因是缺乏针对这些酶中每一种的特异性激活剂、抑制剂或底物。生化、生物物理和分子表征方面的最新进展已经确定了某些结构特征，这些特征对于赋予这些酶对钙离子、二酰甘油或佛波酯以及锌离子的刺激反应很重要；对于阴离子磷脂、钙离子/磷脂复合物和顺式不饱和脂肪酸结合很重要的其他特征尚未得到表征。PKC的激活需要细胞内钙离子浓度（[Ca2+]i）升高以及二酰甘油和/或顺式不饱和脂肪酸。钙离子促进PKC的钙依赖性亚组与膜磷脂酰丝氨酸（PS）的相互作用，当这些酶同时与磷脂酰肌醇4,5-二磷酸结合时会部分激活，而当有二酰甘油时则会完全激活。由磷脂酶A2激活产生的游离脂肪酸，如花生四烯酸，可以与二酰甘油协同作用，最大程度地激活该酶。在二酰甘油水平升高时，PKC的钙非依赖性亚组与PS结合时也会变得活跃。PKC的持续激活会导致这些酶转化为膜插入和膜蛋白相关形式，这可能负责某些长期的神经反应。PKC的激活导致细胞蛋白的磷酸化；其中，几种钙调蛋白（CaM）结合蛋白是这些激酶的主要底物。PKC对这些蛋白的磷酸化有利于钙调蛋白的释放，而钙调蛋白是钙离子/钙调蛋白依赖性酶所必需的。因此，PKC的激活可以通过这种放大步骤导致多种细胞反应。未来的研究应致力于阐明体内每种PKC同工型的激活与生理反应之间的相关性。
