Serine 209 resides within a putative p38(MAPK) consensus motif and regulates monoamine oxidase-A activity.

Full Abstract

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.

Author information

Author/s: Cao, Xia (X); 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);

Affiliation: Cell Signalling Laboratory, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: Journal of neurochemistry (J Neurochem), published in England. (Language: eng)

Reference: 2009-Oct; vol 111 (issue 1) : pp 101-10

Dates: Created 2009/09/23; Completed 2009/10/09;

PMID: 19650872, status: MEDLINE (last retrieved date: 10/9/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Imidazoles - pharmacology
Mice
Mitogen-Activated Protein Kinase 11 - metabolism
Monoamine Oxidase - genetics; metabolism
Neurons - drug effects; metabolism
Phosphorylation - physiology
Pregnancy
Pyridines - pharmacology
RNA, Messenger - metabolism
Rats
Rats, Sprague-Dawley
Serine - genetics; metabolism
Signal Transduction - physiology
Transfection - methods

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Benzimidazoles (0) ; Carbocyanines (0) ; Enzyme Inhibitors (0) ; Imidazoles (0) ; Pyridines (0) ; RNA, Messenger (0) ; SB 203580 (0) ; Clorgyline (17780-72-2) ; 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine (21527-78-6) ; Serine (56-45-1) ; Calcium (7440-70-2) ; Monoamine Oxidase (EC 1.4.3.4) ; Mitogen-Activated Protein Kinase 11 (EC 2.7.1.37)

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