Presenilin regulates capacitative calcium entry dependently and independently of γ-secretase activity
Presenilin regulates capacitative calcium entry dependently and independently of γ-secretase activity
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DOI：
10.1016/j.bbrc.2004.07.136
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发表时间：
2004-10-01
影响因子：
3.1
通讯作者：
LaFerla, FM
中科院分区：
文献类型：
--
作者：
Akbari, Y;Hitt, BD;LaFerla, FM
早老蛋白-1 和 2 (PS) 的突变导致细胞内钙储存增加，以及称为电容性钙进入 (CCE) 的再填充机制减弱。先前的研究表明，PS 调节细胞内钙信号传导的机制依赖于 γ 分泌酶活性。尽管细胞内钙信号传导的调节可以导致 CCE 的改变，但 PS 也可能直接影响 CCE，而与其对细胞内储存的影响无关。为了研究这种可能性，我们研究了称为 DeltaTM1-2 的 PSI 显性失活变体的影响，该变体缺乏 PSI 的前两个跨膜结构域，并且其中γ分泌酶活性被消除。我们证明，与 PSI 的其他显性失活亚型一样，DeltaTM1-2 表达会导致细胞内钙减少。然而，与其他显性负亚型不同，DeltaTM1-2 导致 CCE 的缺陷而不是增强。这些数据表明，早老素结构成分的变化可以独立于其在γ-分泌酶活性和细胞内钙储存中的功能来调节CCE。 (C) 2004 Elsevier Inc. 保留所有权利。
Mutations in presenilin-1 and 2 (PS) lead to increased intracellular calcium stores and an attenuation in the refilling mechanism known as capacitative calcium entry (CCE). Previous studies have shown that the mechanism by which PS modulates intracellular calcium signaling is dependent on gamma-secretase activity. Although the modulation of intracellular calcium signaling can lead to alterations in CCE, it is plausible that PS can also directly affect CCE independent of the effect it exerts on intracellular stores. To investigate this possibility, we studied the effects of the dominant negative variant of PSI known as DeltaTM1-2, which lacks the first two transmembrane domains of PSI and in which gamma-secretase activity is abrogated. We demonstrate that, like other dominant negative isoforms of PSI, DeltaTM1-2 expression leads to reduced intracellular calcium. However, unlike other dominant negative isoforms, DeltaTM1-2 leads to a deficit rather than a potentiation of CCE. These data suggest that changes in the structural components of presenilin can modulate CCE independent of its function in gamma-secretase activity and intracellular calcium stores. (C) 2004 Elsevier Inc. All rights reserved.