Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity.
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.
Cao
Xia
X
Cell Signalling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Rui
Lewei
L
Pennington
Paul R
PR
Chlan-Fourney
Jennifer
J
Jiang
Zhongjian
Z
Wei
Zelan
Z
Li
Xin-Min
XM
Edmondson
Dale E
DE
Mousseau
Darrell D
DD
D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002232:Carbocyanines / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003010:Clorgyline / Q000494:pharmacology; D016384:Consensus Sequence; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D048290:Mitogen-Activated Protein Kinase 11 / Q000378:metabolism*; D008995:Monoamine Oxidase / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D011247:Pregnancy; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection / Q000379:methods
D001562:Benzimidazoles; D002232:Carbocyanines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D012694:Serine; D008995:Monoamine Oxidase; D048290:Mitogen-Activated Protein Kinase 11; D003010:Clorgyline; C093642:SB 203580; D002118:Calcium