The potential role of caveolin-1 in inhibition of aquaporins during the AVID
The potential role of caveolin-1 in inhibition of aquaporins during the AVID
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DOI：
10.1042/bc20040131
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发表时间：
2006-01-01
影响因子：
2.7
通讯作者：
Hughes, FM
中科院分区：
文献类型：
--
作者：
Jablonski, EM;Hughes, FM
背景资料。在凋亡过程中，第一个形态学变化是称为AVD（凋亡体积减少）的明显细胞收缩。该事件由细胞内K+的损失驱动，其产生渗透梯度，通过AQP（水通道蛋白）将水从细胞中抽出。与K+平衡的水的损失将产生具有等效细胞内K+浓度（[K+]（i）= 140 mM）的收缩细胞。然而，我们以前已经表明，[K+]（i）的萎缩凋亡细胞是35 mM，这个水平是绝对必要的凋亡酶的激活。我们最近发现AQP在AVID后失活，因此K+的持续丢失将使细胞内浓度降低到这一临界水平。利用胸腺细胞，我们研究了AQP家族成员的表达谱和调控。在本研究中，我们发现，AQP 1，AQP 8和AQP 9存在于非凋亡的胸腺细胞和主要定位于质膜。当这些细胞通过生长因子去除24 h诱导凋亡时，表达和定位没有改变。为了探索这些水通道失活的其他可能机制，我们研究了它们与CAV-1（小窝蛋白-1）的关系，已知与CAV-1的结合可以抑制多种蛋白质。我们发现CAV-1存在于胸腺细胞中，并且这种蛋白质与正常（非凋亡）胸腺细胞中的AQP 1的一部分共定位。然而，诱导胸腺细胞凋亡大大增加了它们的AQP 1/CAV-1联系。综上所述，这些结果表明，AQPs定位于萎缩的凋亡胸腺细胞的质膜，其中增加与CAV-1的结合可能使它们失活。AQP失活，再加上持续的K+外流，然后允许[K+]（i）降低到有利于激活下游凋亡酶和完成凋亡级联反应的水平。
Background information. During apoptosis, the first morphological change is a distinct cell shrinkage known as the AVD (apoptotic volume decrease). This event is driven by a loss of intracellular K+, which creates an osmotic gradient, drawing water out of the cell through AQPs (aquaporins). Loss of water in balance with K+ would create a shrunken cell with an equivalent intracellular concentration of K+([K+](i) = 140 mM). However, we have previously shown that the [K+](i) of the shrunken apoptotic cell is 35 mM, and this level is absolutely essential for the activation of apoptotic enzymes. We have recently found that AQPs are inactivated following the AVID, so that continued loss of K+ will reduce the intracellular concentration to this critical level. Using thymocytes, we have investigated the expression profile and regulation of the AQP family members.Results. In the present study, we have found that AQP1, AQP8 and AQP9 are present in non-apoptotic thymocytes and localized primarily to the plasma membrane. Expression and localization did not change when these cells were induced to undergo apoptosis by growth factor withdrawal for 24 h. To explore other possible mechanisms by which these water channels are inactivated, we investigated their association with CAV-1 (caveolin-1), binding to which is known to inactivate a variety of proteins. We found that CAV-1 is present in thymocytes and that this protein co-localizes with a portion of AQP1 in normal (non-apoptotic) thymocytes. However, thymocytes induced to undergo apoptosis greatly increase their AQP1/CAV-1 association.Conclusions. Taken together, these results indicate that AQPs are localized to the plasma membrane of shrunken apoptotic thymocytes where increased binding to CAV-1 potentially inactivates them. AQP inactivation, coupled with continued K+ efflux, then allows the [K+](i) to decrease to levels conducive for the activation of downstream apoptotic enzymes and the completion of the apoptotic cascade.