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首页> 外文期刊>American Journal of Physiology >TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage.
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TRPM2 is an ion channel that modulates hematopoietic cell death through activation of caspases and PARP cleavage.

机译：TRPM2是一个离子通道，可通过激活半胱氨酸蛋白酶和PARP酶来调节造血细胞的死亡。

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TRPM2 is a Ca(2+)-permeable channel activated by oxidative stress or TNF-alpha, and TRPM2 activation confers susceptibility to cell death. The mechanisms were examined here in human monocytic U937-ecoR cells. This cell line expresses full-length TRPM2 (TRPM2-L) and several isoforms including a short splice variant lacking the Ca(2+)-permeable pore region (TRPM2-S), which functions as a dominant negative. Treatment with H(2)O(2), a model of oxidative stress, or TNF-alpha results in reduced cell viability. Expression of TRPM2-L and TRPM2-S was modulated by retroviral infection. U937-ecoR cells expressing increased levels of TRPM2-L were treated with H(2)O(2) or TNF-alpha, and these cells exhibited significantly increased intracellular calcium concentration ([Ca(2+)](i)), decreased viability, and increased apoptosis. A dramatic increase in cleavage of caspases-8, -9, -3, and -7 and poly(ADP-ribose)polymerase (PARP) was observed, demonstrating a downstream mechanism through which cell death is mediated. Bcl-2 levels were unchanged. Inhibition of the [Ca(2+)](i) rise with the intracellular Ca(2+) chelator BAPTA blocked caspase/PARP cleavage and cell death induced after activation of TRPM2-L, demonstrating the critical role of [Ca(2+)](i) in mediating these effects. Downregulation of endogenous TRPM2 by RNA interference or increased expression of TRPM2-S inhibited the rise in [Ca(2+)](i), enhanced cell viability, and reduced numbers of apoptotic cells after exposure to oxidative stress or TNF-alpha, demonstrating the physiological importance of TRPM2. Our data show that one mechanism through which oxidative stress or TNF-alpha mediates cell death is activation of TRPM2, resulting in increased [Ca(2+)](i), followed by caspase activation and PARP cleavage. Inhibition of TRPM2-L function by reduction in TRPM2 levels, interaction with TRPM2-S, or Ca(2+) chelation antagonizes this important cell death pathway.
机译：TRPM2是被氧化应激或TNF-α激活的Ca（2+）渗透通道，TRPM2激活赋予细胞死亡易感性。在人单核细胞U937-ecoR细胞中检查了该机制。此细胞系表达全长TRPM2（TRPM2-L）和几种同工型，包括缺少Ca（2 +）-可渗透孔区域（TRPM2-S）的短剪接变体，其起显性负性作用。 H（2）O（2），氧化应激模型或TNF-α的治疗导致细胞活力降低。 TRPM2-L和TRPM2-S的表达受逆转录病毒感染的调节。用H（2）O（2）或TNF-α处理表达TRPM2-L水平升高的U937-ecoR细胞，这些细胞的细胞内钙浓度（[Ca（2 +）]（i）显着增加，降低活力，并增加细胞凋亡。观察到胱天蛋白酶8，-9，-3和-7和聚（ADP-核糖）聚合酶（PARP）的切割的急剧增加，表明了介导细胞死亡的下游机制。 Bcl-2水平未改变。抑制[Ca（2 +）]（i）上升与细胞内Ca（2+）螯合剂BAPTA阻断caspase / PARP裂解和激活TRPM2-L后诱导的细胞死亡，证明了[Ca（2+）的关键作用）]（i）调解这些影响。 RNA干扰或TRPM2-S的表达增加对内源性TRPM2的下调抑制了[Ca（2 +）]（i）的升高，增强了细胞活力，并减少了氧化应激或TNF-α暴露后凋亡细胞的数量，证明了TRPM2的生理重要性。我们的数据表明，氧化应激或TNF-α介导细胞死亡的一种机制是TRPM2的激活，从而导致[Ca（2 +）]（i）增加，然后是caspase激活和PARP裂解。通过降低TRPM2水平，与TRPM2-S或Ca（2+）螯合相互作用来抑制TRPM2-L功能可拮抗这一重要的细胞死亡途径。

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