P38(MAPK) negatively regulates monoamine oxidase-A activity as well as its sensitivity to Ca2+
| dc.contributor.advisor | Mousseau, Darrell D. | en_US |
| dc.contributor.advisor | Li, Xin-Min | en_US |
| dc.contributor.committeeMember | Nazarali, Adil J. | en_US |
| dc.contributor.committeeMember | Kalynchuk, Lisa E. | en_US |
| dc.contributor.committeeMember | Baker, Glen | en_US |
| dc.contributor.committeeMember | Yu, Peter H. | en_US |
| dc.creator | Cao, Xia | en_US |
| dc.date.accessioned | 2008-01-03T12:16:37Z | en_US |
| dc.date.accessioned | 2013-01-04T04:23:07Z | |
| dc.date.available | 2009-01-04T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T04:23:07Z | |
| dc.date.created | 2007 | en_US |
| dc.date.issued | 2007 | en_US |
| dc.date.submitted | 2007 | en_US |
| dc.description.abstract | Monoamine oxidase (MAO) is a mitochondrial deaminating enzyme that exists as two isoforms, MAO-A and -B. The MAO-mediated reaction generates hydrogen peroxide (H2O2) as a normal by-product. Dysregulation of MAO has been implicated in a variety of neuropsychiatric and neurodegenerative disorders, as well as in the aging process. Endogenous regulators of MAO-A function include calcium (Ca2+) and the p38 mitogen-activated protein kinase (MAPK). Although the effect of p38(MAPK) is thought to rely on induction of mao-A gene expression, post-translational modification of the MAO-A protein is also possible. Using standard biochemical approaches in combination with pharmacological interventions and recombinant DNA strategies, specific aspartic acid residues (within putative Ca2+-binding motifs) were demonstrated to contribute to MAO-A activity. Furthermore, MAO-A activity and its sensitivity to Ca2+ was negatively regulated by the p38(MAPK), which is usually activated during cell stress. The effect of p38(MAPK) on MAO-A function relies specifically on Serine209 in MAO-A, which resides in a p38(MAPK) consensus motif. The serine phosphorylation status of MAO-A determines its capacity for generating peroxy radicals and its toxicity in established cell lines (e.g. C6, N2a, HEK293A, HT-22) and in primary cortical neurons. p38(MAPK)-regulated MAO-A activity is also linked to neurotoxicity associated with the Alzheimer disease-related peptide, ƒÒ-amyloid (AƒÒ). These data suggest a unique neuroprotective role for p38(MAPK) centered on a negative feedback regulation of the Ca2+-sensitive, H2O2-generating enzyme MAO-A. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-01032008-121637 | en_US |
| dc.language.iso | en_US | en_US |
| dc.subject | Phosphorylation | en_US |
| dc.subject | p38 MAP Kinase | en_US |
| dc.subject | Mitochondria | en_US |
| dc.subject | Calcium | en_US |
| dc.subject | Mutagenesis | en_US |
| dc.subject | Apoptosis | en_US |
| dc.subject | Hydrogen Peroxide | en_US |
| dc.subject | Activity | en_US |
| dc.subject | Monoamine Oxidase | en_US |
| dc.title | P38(MAPK) negatively regulates monoamine oxidase-A activity as well as its sensitivity to Ca2+ | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Psychiatry | en_US |
| thesis.degree.discipline | Psychiatry | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |