Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
Clin Exp Pharmacol Physiol. 2012 Aug;39(8):684-91. doi: 10.1111/j.1440-1681.2011.05621.x.
Excitotoxicity, a major cause of neuronal death in acute and chronic neurodegenerative diseases and conditions such as stroke and Parkinson's disease, is initiated by overstimulation of glutamate receptors, leading to calcium overload in affected neurons. The sustained high concentration of intracellular calcium constitutively activates a host of enzymes, notably the calcium-activated proteases calpains, neuronal nitric oxide synthase (nNOS) and NADPH oxidase (NOX), to antagonise the cell survival signalling pathways and induce cell death. Upon overactivation by calcium, calpains catalyse limited proteolysis of specific cellular proteins to modulate their functions; nNOS produces excessive amounts of nitric oxide (NO), which, in turn, covalently modifies specific enzymes by S-nitrosylation; and NOX produces excessive amounts of reactive oxygen species (ROS) to inflict damage to key metabolic enzymes. Presumably, key regulatory enzymes governing cell survival and cell death are aberrantly modified and regulated by calpains, NO and ROS in affected neurons; these aberrantly modified enzymes then cooperate to induce the death of affected neurons. c-Src, an Src family kinase (SFK) member, is one of the aberrantly regulated enzymes involved in excitotoxic neuronal death. Herein we review how SFKs are functionally linked to the glutamate receptors and the biochemical and structural basis of the aberrant regulation of SFKs. Results in the literature suggest that SFKs are aberrantly activated by calpain-mediated truncation and S-nitrosylation. Thus, the aberrantly activated SFKs are targets for therapeutic intervention to reduce the extent of brain damage caused by stroke.
兴奋性毒性是急性和慢性神经退行性疾病和中风、帕金森病等疾病状态中神经元死亡的主要原因，它是由谷氨酸受体过度刺激引起的，导致受影响神经元中的钙超载。细胞内钙的持续高浓度会持续激活大量酶，特别是钙激活的蛋白酶钙蛋白酶、神经元型一氧化氮合酶（nNOS）和 NADPH 氧化酶（NOX），以拮抗细胞存活信号通路并诱导细胞死亡。钙过度激活后，钙蛋白酶催化特定细胞蛋白的有限蛋白水解，以调节其功能；nNOS 产生过量的一氧化氮（NO），NO 又通过 S-亚硝基化共价修饰特定的酶；NOX 产生过量的活性氧（ROS），对关键代谢酶造成损伤。据推测，受影响神经元中控制细胞存活和细胞死亡的关键调节酶被钙蛋白酶、NO 和 ROS 异常修饰和调节；这些异常修饰的酶随后协同诱导受影响神经元的死亡。c-Src 是Src 家族激酶（SFK）成员之一，是参与兴奋性毒性神经元死亡的异常调节酶之一。本文综述了 SFK 如何与谷氨酸受体功能相关联，以及 SFK 异常调节的生化和结构基础。文献中的结果表明，SFK 被钙蛋白酶介导的截断和 S-亚硝基化异常激活。因此，异常激活的 SFK 是治疗干预的靶点，可以减少中风引起的脑损伤程度。
