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首页> 外文期刊>The European Journal of Neuroscience >Depolarization regulates cyclin D1 degradation and neuronal apoptosis: a hypothesis about the role of the ubiquitin/proteasome signalling pathway.
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Depolarization regulates cyclin D1 degradation and neuronal apoptosis: a hypothesis about the role of the ubiquitin/proteasome signalling pathway.

机译：去极化调节细胞周期蛋白D1降解和神经元凋亡：关于泛素/蛋白酶体信号通路作用的假设。

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Depolarization and subsequent calcium entry exert essential neuroprotective effects but the ultimate effector by which calcium blocks apoptosis is not known. Here we show that inhibition of calcium entry into cerebellar neurons by switching from high to low extracellular K+ concentrations (30-5 mM) induces apoptosis, that correlates with a rapid accumulation of cyclin D1 (CD1), an early marker of the G1/S transition of the cell cycle. These effects on apoptosis and cyclin D1 are mimicked either by blocking calcium entry into neurons (LaCl3, 100 microM or nifedipine, 10(-6) M) or by inhibiting the calcium/calmodulin pathway (calmidazolium, 10(-7) M). The increased CD1 protein levels do not result from a transcriptional upregulation of the CD1 gene by the Ca2+/calmodulin pathway but rather reflect an accumulation due to the lack of degradation by the proteasome-dependent pathway. Specific proteasome antagonists: carbobenzoxyl-leucinyl-leucinyl-norvalinal-H (MG-115), carbobenzoxyl-leucinyl-leucinyl-leucinal-H (MG-132) and clastolactacystin beta-lactone, induce neuronal apoptosis by themselves. Finally, this pathway is functional only at neuroprotective concentrations of K+ (30 mM), suggesting that calcium/CamK signalling pathway may regulate neuronal death by regulating the proteasome-mediated degradation activity of rapidly turning-over proteins (constitutively expressed genes or pre-existing pools of mRNA).
机译：去极化和随后的钙进入发挥基本的神经保护作用，但钙阻断细胞凋亡的最终效应器尚不清楚。在这里我们表明，通过从高到低的细胞外K +浓度（30-5 mM）切换来抑制钙进入小脑神经元会诱导凋亡，这与细胞周期蛋白D1（CD1）（G1 / S的早期标记）的快速积累相关细胞周期的过渡。通过阻止钙进入神经元（LaCl3、100 microM或硝苯地平（10（-6）M）或通过抑制钙/钙调蛋白途径（钙mid，10（-7）M）来模仿对凋亡和细胞周期蛋白D1的这些作用。增加的CD1蛋白水平不是由Ca2 + /钙调蛋白途径对CD1基因的转录上调引起的，而是反映了由于缺乏蛋白酶体依赖性途径引起的降解而导致的积累。特定的蛋白酶体拮抗剂：羧苯甲酰基-亮氨酰-亮氨酸-norvalinal-H（MG-115），羧苯甲酰基-亮氨酰-亮氨酸-亮氨酸-H（MG-132）和锁骨乳杆菌抑制素-β-内酯自己诱导神经元凋亡。最后，该途径仅在K +（30 mM）的神经保护浓度下起作用，这表明钙/ CamK信号传导途径可通过调节蛋白酶体介导的快速翻转蛋白（组成型表达的基因或预先存在的蛋白）的降解活性来调节神经元死亡。 mRNA池）。

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