Cao X, Rui L, Pennington P, Chlan-Fourney J, Jiang Z, Wei Z, Li XM, Edmondson DE, Mousseau DD
Serine209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity. [JOURNAL ARTICLE]
J Neurochem 2009 Jul 23.
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. Overexpression 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 overexpressed 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 disease.
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