Brostrom Margaret A, Brostrom Charles O
Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Cell Calcium. 2003 Oct-Nov;34(4-5):345-63. doi: 10.1016/s0143-4160(03)00127-1.
The endoplasmic reticulum (ER) possesses the structural and functional features expected of an organelle that supports the integration and coordination of major cellular processes. Ca(2+) sequestered within the ER sustains lumenal protein processing while providing a reservoir of the cation to support stimulus-response coupling in the cytosol. Release of ER Ca(2+) sufficient to impair protein processing promotes ER stress and signals the "unfolded protein response" (UPR). The association of the UPR with an acute suppression of mRNA translational initiation and a longer term up-regulation of ER chaperones and partial translational recovery is discussed. Regulatory sites in mRNA translation and the mechanisms responsible for the early and later phases of the UPR are reviewed. The regulatory significance of GRP78/BiP, a multifunctional, broad-specificity ER chaperone, in the coordination of ER protein processing with mRNA translation during acute and chronic ER stress is addressed. The relationship of ER stress to protein misfolding in the cytoplasm is examined. Translational alterations in embryonic cardiomyocytes during treatments with various Ca(2+)-mobilizing, growth-promoting stimuli are described. The importance of ER Ca(2+) stores, ER chaperones, and cytosolic-free Ca(2+) in translational control and growth promotion by these stimuli is assessed. Some perspectives are provided regarding Ca(2+) as an integrating factor in the generation or diversion of metabolic energy. Circumstances impacting upon cellular adaptability during exposure to growth stimuli or during stressful conditions that require rapid adjustments in ATP for continued viability are considered.
内质网（ER）具备作为支持主要细胞过程整合与协调的细胞器所应有的结构和功能特征。内质网中螯合的Ca(2+)维持着腔内蛋白质加工过程，同时为阳离子提供储存库以支持胞质溶胶中的刺激-反应偶联。内质网Ca(2+)的释放若足以损害蛋白质加工，则会引发内质网应激并发出“未折叠蛋白反应”（UPR）信号。本文讨论了UPR与mRNA翻译起始的急性抑制以及内质网伴侣蛋白的长期上调和部分翻译恢复之间的关联。综述了mRNA翻译中的调控位点以及负责UPR早期和后期阶段的机制。探讨了多功能、广泛特异性的内质网伴侣蛋白GRP78/BiP在急性和慢性内质网应激期间内质网蛋白质加工与mRNA翻译协调中的调控意义。研究了内质网应激与细胞质中蛋白质错误折叠的关系。描述了在各种Ca(2+)动员、生长促进刺激处理过程中胚胎心肌细胞的翻译改变。评估了内质网Ca(2+)储存、内质网伴侣蛋白和胞质游离Ca(2+)在这些刺激的翻译控制和生长促进中的重要性。提供了一些关于Ca(2+)作为代谢能量产生或转移的整合因子的观点。考虑了在暴露于生长刺激期间或在需要快速调整ATP以维持生存能力的应激条件下影响细胞适应性的情况。
