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Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase‐A activity
Author(s) -
Cao Xia,
Rui Lewei,
Pennington Paul R.,
ChlanFourney Jennifer,
Jiang Zhongjian,
Wei Zelan,
Li XinMin,
Edmondson Dale E.,
Mousseau Darrell D.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06300.x
Subject(s) - monoamine oxidase , mapk/erk pathway , phosphorylation , biology , p38 mitogen activated protein kinases , protein kinase a , microbiology and biotechnology , biochemistry , enzyme
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.