Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity
Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity
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DOI：
10.1111/j.1471-4159.2009.06300.x
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发表时间：
2009-10-01
影响因子：
4.7
通讯作者：
Mousseau, Darrell D.
中科院分区：
文献类型：
--
作者：
Cao, Xia;Rui, Lewei;Mousseau, Darrell D.
p38丝裂原活化蛋白激酶（MAPK）级联以及单胺氧化酶-A（MAO-A）都与氧化应激有关。我们观察到，p38（MAPK）蛋白的特异性抑制[使用化学抑制剂或显性负性p38（MAPK）克隆]选择性诱导MAO-A活性和MAO-A敏感性毒性在几个神经元细胞系，包括原代皮层神经元。组成型活性p38（MAPK）的过表达导致MAO-A蛋白的磷酸化和MAO-A活性的抑制。MAO-A（Ser 209 Glu）磷酸模拟物-在推定的p38（MAPK）共有基序内具有靶向取代-既没有活性也没有神经毒性。相比之下，MAO-A（Ser 209 Ala）变体（模拟去磷酸化）不与p38（MAPK）相关，并且非常活跃且毒性很大。用Glu或Ala取代MAO-B同种型中的同源丝氨酸，即Ser 200，不影响相应过表达蛋白的催化活性。这些组合的体外数据强烈表明MAO-A功能的直接p38（MAPK）依赖性抑制。基于已发表的观察结果，这种选择性调节MAO-A功能的内源性手段可以提供对与抑郁症、再灌注/缺血和阿尔茨海默病早期等多种疾病相关的氧化应激的适应性反应。
The p38 mitogen-activated protein kinase (MAPK) cascade as well as the enzyme monoamine oxidase-A (MAO-A) have both been associated with oxidative stress. We observed that the specific inhibition of the p38(MAPK) protein [using either a chemical inhibitor or a dominant-negative p38(MAPK) clone] selectively induces MAO-A activity and MAO-A-sensitive toxicity in several neuronal cell lines, including primary cortical neurons. Over-expression of a constitutively active p38(MAPK) results in the phosphorylation of the MAO-A protein and inhibition of MAO-A activity. The MAO-A(Ser209Glu) phosphomimic - bearing a targeted substitution within a putative p38(MAPK) consensus motif - is neither active nor neurotoxic. In contrast, the MAO-A(Ser209Ala) variant (mimics dephosphorylation) does not associate with p38(MAPK), and is both very active and very toxic. Substitution of the homologous serine in the MAO-B isoform, i.e. Ser200, with either Glu or Ala does not affect the catalytic activity of the corresponding over-expressed proteins. These combined in vitro data strongly suggest a direct p38(MAPK)dependent inhibition of MAO-A function. Based on published observations, this endogenous means of selectively regulating MAO-A function could provide for an adaptive response to oxidative stress associated with disorders as diverse as depression, reperfusion/ischemia, and the early stages of Alzheimer's disease.