p38(MAPK) Negatively Regulates Monoamine Oxidase-A Activity As Well As Its Sensitivity To Ca2+.
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, Ò-amyloid (AÒ). 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.
Advisor:Baker, Glen; Li, Xin-Min; Kalynchuk, Lisa; Yu, Peter; Nazarali, Adil; Mousseau, Darrell D.
School:University of Saskatchewan
School Location:Canada - Saskatchewan
Source Type:Master's Thesis
Keywords:phosphorylation p38 map kinase mitochondria calcium mutagenesis apoptosis hydrogen peroxide activity monoamine oxidase
Date of Publication:01/04/2008