Paschen Wulf
Department of Experimental Neurology, Max-Planck-Institute for Neurological Research, 50931 Koeln, Germany.
Cell Calcium. 2003 Oct-Nov;34(4-5):365-83. doi: 10.1016/s0143-4160(03)00139-8.
Changes in neuronal calcium activity in the various subcellular compartments have divergent effects on affected cells. In the cytoplasm and mitochondria, where calcium activity is normally low, a prolonged excessive rise in free calcium levels is believed to be toxic, in the endoplasmic reticulum (ER), in contrast, calcium activity is relatively high and severe stress is caused by a depletion of ER calcium stores. Besides its role in cellular calcium signaling, the ER is the site where membrane and secretory proteins are folded and processed. These calcium-dependent processes are fundamental to normal cell functioning. Under conditions of ER dysfunction unfolded proteins accumulate in the ER lumen, a signal responsible for activation of the unfolded protein response (UPR) and the ER-associated degradation (ERAD). UPR is characterized by activation of two ER-resident kinases, PKR-like ER kinase (PERK) and IRE1. PERK induces phosphorylation of the eukaryotic initiation factor (eIF2alpha), resulting in a shut-down of translation at the initiation step. This stress response is needed to block new synthesis of proteins that cannot be correctly folded, and thus to protect cells from the effect of unfolded proteins which tend to form toxic aggregates. IRE1, on the other hand, is turned after activation into an endonuclease that cuts out a sequence of 26 bases from the coding region of xbp1 mRNA. Processed xbp1 mRNA is translated into the respective protein, an active transcription factor specific for ER stress genes such as grp78. In acute disorders and degenerative diseases, the ER calcium pool is a primary target of toxic metabolites or intermediates, such as oxygen free radicals, produced during the pathological process. Affected neurons need to activate the entire UPR to cope with the severe form of stress induced by ER dysfunction. This stress response is however hindered under conditions where protein synthesis is suppressed to such an extent that processed xbp1 mRNA is not translated into the processed XBP1 protein (XBP1(proc)). Furthermore, activation of ERAD is important for the degradation of unfolded proteins through the ubiquitin/proteasomal pathway, which is impaired in acute disorders and degenerative diseases, resulting in further ER stress. ER functioning is thus impaired in two different ways: first by the direct action of toxic intermediates, produced in the course of the pathological process, hindering vital ER reactions, and second by the inability of cells to fully activate UPR and ERAD, leaving them unable to withstand the severe form of stress induced by ER dysfunction.
神经元钙活性在不同亚细胞区室的变化对受影响细胞具有不同影响。在细胞质和线粒体中，钙活性通常较低，游离钙水平的长时间过度升高被认为具有毒性，而在内质网（ER）中，情况则相反，钙活性相对较高，内质网钙储存耗竭会导致严重应激。除了在细胞钙信号传导中的作用外，内质网还是膜蛋白和分泌蛋白折叠与加工的场所。这些依赖钙的过程对于正常细胞功能至关重要。在内质网功能障碍的情况下，未折叠蛋白会在内质网腔中积累，这是激活未折叠蛋白反应（UPR）和内质网相关降解（ERAD）的信号。UPR的特征是激活两种内质网驻留激酶，即PKR样内质网激酶（PERK）和肌醇需求酶1（IRE1）。PERK诱导真核起始因子（eIF2α）磷酸化，导致翻译在起始步骤关闭。这种应激反应是为了阻止无法正确折叠的蛋白质的新合成，从而保护细胞免受倾向于形成有毒聚集体的未折叠蛋白的影响。另一方面，IRE1激活后会变成一种核酸内切酶，从xbp1 mRNA的编码区切出一段26个碱基的序列。加工后的xbp1 mRNA会被翻译成相应的蛋白质，一种对内质网应激基因（如grp78）具有特异性的活性转录因子。在急性疾病和退行性疾病中，内质网钙库是病理过程中产生的有毒代谢产物或中间体（如氧自由基）的主要靶点。受影响的神经元需要激活整个UPR来应对内质网功能障碍引起的严重应激形式。然而，在蛋白质合成被抑制到加工后的xbp1 mRNA无法翻译成加工后的XBP1蛋白（XBP1(proc)）的情况下，这种应激反应会受到阻碍。此外，ERAD的激活对于通过泛素/蛋白酶体途径降解未折叠蛋白很重要，而在急性疾病和退行性疾病中该途径受损，导致内质网进一步应激。因此，内质网功能以两种不同方式受损：一是病理过程中产生的有毒中间体的直接作用，阻碍内质网的重要反应；二是细胞无法完全激活UPR和ERAD，使其无法承受内质网功能障碍引起的严重应激形式。
