Nelson Thomas J, Sun Miao-Kun, Hongpaisan Jarin, Alkon Daniel L
Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Rockville, Maryland 20850 USA.
Eur J Pharmacol. 2008 May 6;585(1):76-87. doi: 10.1016/j.ejphar.2008.01.051. Epub 2008 Mar 4.
Protein kinase C (PKC) is involved in synaptic remodeling, induction of protein synthesis, and many other processes important in learning and memory. Activation of neuronal protein kinase C correlates with, and may be essential for, all phases of learning, including acquisition, consolidation, and reconsolidation. Protein kinase C activation is closely tied to hydrolysis of membrane lipids. Phospholipases C and A2 produce 1,2-diacylglycerol and arachidonic acid, which are direct activators of protein kinase C. Phospholipase C also produces inositol triphosphate, which releases calcium from internal stores. Protein kinase C interacts with many of the same pathways as insulin; therefore, it should not be surprising that insulin signaling and protein kinase C activation can both have powerful effects on memory storage and synaptic remodeling. However, investigating the possible roles of insulin in memory storage can be challenging, due to the powerful peripheral effects of insulin on glucose and the low concentration of insulin in the brain. Although peripheral for insulin, synthesized in the beta-cells of the pancreas, is primarily involved in regulating glucose, small amounts of insulin are also present in the brain. The functions of this brain insulin are inadequately understood. Protein kinase C may also contribute to insulin resistance by phosphorylating the insulin receptor substrates required for insulin signaling. Insulin is also responsible insulin-long term depression, a type of synaptic plasticity that is also dependent on protein kinase C. However, insulin can also activate PKC signaling pathways via PLC gamma, Erk 1/2 MAP kinase, and src stimulation. Taken together, the available evidence suggests that the major impact of protein kinase C and its interaction with insulin in the mature, fully differentiated nervous system appears to be to induce synaptogenesis, enhance memory, reduce Alzheimer's pathophysiology, and stimulate neurorepair.
蛋白激酶C（PKC）参与突触重塑、蛋白质合成诱导以及许多其他对学习和记忆至关重要的过程。神经元蛋白激酶C的激活与学习的所有阶段相关，并且可能是必不可少的，包括获取、巩固和再巩固。蛋白激酶C的激活与膜脂的水解密切相关。磷脂酶C和A2产生1,2 - 二酰甘油和花生四烯酸，它们是蛋白激酶C的直接激活剂。磷脂酶C还产生肌醇三磷酸，它从内部储存中释放钙。蛋白激酶C与许多与胰岛素相同的信号通路相互作用；因此，胰岛素信号传导和蛋白激酶C激活都能对记忆存储和突触重塑产生强大影响也就不足为奇了。然而，由于胰岛素对葡萄糖有强大的外周作用且大脑中胰岛素浓度较低，研究胰岛素在记忆存储中的可能作用具有挑战性。虽然在胰腺β细胞中合成的外周胰岛素主要参与调节葡萄糖，但大脑中也存在少量胰岛素。人们对这种大脑胰岛素的功能了解不足。蛋白激酶C也可能通过磷酸化胰岛素信号传导所需的胰岛素受体底物导致胰岛素抵抗。胰岛素还与胰岛素长期抑制有关，这是一种也依赖于蛋白激酶C的突触可塑性。然而，胰岛素也可以通过PLCγ、Erk 1/2 MAP激酶和src刺激激活PKC信号通路。综上所述，现有证据表明，在成熟、完全分化的神经系统中，蛋白激酶C及其与胰岛素的相互作用的主要影响似乎是诱导突触形成、增强记忆、减轻阿尔茨海默病的病理生理学并刺激神经修复。
