Oxygen dependence of nitric oxide-mediated signaling.
Oxygen dependence of nitric oxide-mediated signaling.
复制标题
DOI：
10.1016/j.redox.2012.11.002
复制
发表时间：
2013
期刊：
影响因子：
11.4
通讯作者：
Thomas, Douglas D.
中科院分区：
文献类型：
--
作者：
Hickok, Jason R.;Vasudevan, Divya;Jablonski, Kate;Thomas, Douglas D.
一氧化氮（·NO）是一种重要的短寿命自由基信号分子。NO的酶促合成和细胞代谢的主要形式都是氧依赖性的。由于这些原因，局部氧浓度的变化可以对稳态·NO浓度产生深远的影响。许多蛋白质受NO浓度依赖性调节，但它们的反应在不同的阈值引起。利用可溶性鸟苷酸环化酶（sGC）和p53作为模型·NO敏感蛋白，我们证明了它们对·NO的浓度依赖性反应是O2浓度的函数。p53需要相对高的稳态NO浓度（>600 nM）来诱导其磷酸化（P-ser-15），而sGC对低NO浓度（<100 nM）有反应。在恒定的·NO生成速率（从·NO供体释放）下，降低O2浓度（1%）会降低·NO代谢速率。这提高了稳态·NO浓度，并允许在较低剂量的·NO供体下激活p53。然而，酶促·NO产生需要O2作为底物，使得将O2浓度降低到低于O2对一氧化氮合酶（NOS）的Km将降低·NO的产生。我们证明RAW 264.7巨噬细胞产生的·NO的量是O2浓度的函数。·NO产生和·NO代谢速率的差异导致不同的sGC活化，其相对于O2不是线性的。存在一个最佳O2浓度（0.5%-8%），在该浓度下，·NO的合成和代谢之间建立平衡，使得·NO浓度和sGC活化最大。超氧阴离子通过调节·NO的合成和代谢来调节·NO信号转导。NO_2通过调节NOS的表达和底物的利用来影响NO的合成。酶促·NO生成速率在1- 8%O2范围内呈线性增加。③随着[O2]浓度的增加，细胞·NO代谢速率增加。NO介导的sGC激活在5%至8%O2之间最大。
Nitric oxide (•NO) is a biologically important short-lived free radical signaling molecule. Both the enzymatic synthesis and the predominant forms of cellular metabolism of •NO are oxygen-dependent. For these reasons, changes in local oxygen concentrations can have a profound influence on steady-state •NO concentrations. Many proteins are regulated by •NO in a concentration-dependent manner, but their responses are elicited at different thresholds. Using soluble guanylyl cyclase (sGC) and p53 as model •NO-sensitive proteins, we demonstrate that their concentration-dependent responses to •NO are a function of the O2 concentration. p53 requires relatively high steady-state •NO concentrations (>600 nM) to induce its phosphorylation (P-ser-15), whereas sGC responds to low •NO concentrations (<100 nM). At a constant rate of •NO production (liberation from •NO-donors), decreasing the O2 concentration (1%) lowers the rate of •NO metabolism. This raises steady-state •NO concentrations and allows p53 activation at lower doses of the •NO donor. Enzymatic •NO production, however, requires O2 as a substrate such that decreasing the O2 concentration below the Km for O2 for nitric oxide synthase (NOS) will decrease the production of •NO. We demonstrate that the amount of •NO produced by RAW 264.7 macrophages is a function of the O2 concentration. Differences in rates of •NO production and •NO metabolism result in differential sGC activation that is not linear with respect to O2. There is an optimal O2 concentration (≈5–8%) where a balance between the synthesis and metabolism of •NO is established such that both the •NO concentration and sGC activation are maximal. ►► O2 regulates •NO signaling by modulating •NO synthesis and metabolism. ► O2 affects •NO synthesis by regulating NOS expression and substrate availability. ► The rate of enzymatic •NO production increases linearly from 1–8% O2. ► The rate of cellular •NO metabolism increases with increasing [O2]. ► •NO-mediated sGC activation is maximal between 5% and 8% O2.
登录
查看更多内容
影响因子：
3.1
作者：
Hickok JR;Thomas DD
通讯作者：
Thomas DD
DOI：
10.1073/pnas.0400453101
发表时间：
2004-06-15
影响因子：
11.1
作者：
Thomas, DD;Espey, MG;Wink, DA
通讯作者：
Wink, DA
DOI：
10.1073/pnas.012368499
发表时间：
2002-01-08
影响因子：
11.1
作者：
Bellamy, TC;Wood, J;Garthwaite, J
通讯作者：
Garthwaite, J
DOI：
10.1073/pnas.98.1.355
发表时间：
2001-01-02
影响因子：
11.1
作者：
Thomas, DD;Liu, ZP;Lancaster, JR
通讯作者：
Lancaster, JR
影响因子：
7.4
作者：
Hickok, Jason R.;Sahni, Sumit;Thomas, Douglas D.
通讯作者：
Thomas, Douglas D.