Oxidation of calmodulin alters activation and regulation of CaMKII.
Increases in reactive oxygen species and mis-regulation of calcium homeostasis are associated with various physiological conditions and disease states including aging, ischemia, exposure to drugs of abuse, and neurodegenerative diseases. In aged animals, this is accompanied by a reduction in oxidative repair mechanisms resulting in increased methionine oxidation of the calcium signaling protein calmodulin in the brain. Here, we show that oxidation of calmodulin results in an inability to: (1) activate CaMKII; (2) support Thr(286) autophosphorylation of CaMKII; (3) prevent Thr(305/6) autophosphorylation of CaMKII; (4) support binding of CaMKII to the NR2B subunit of the NMDA receptor; and (5) compete with alpha-actinin for binding to CaMKII. Moreover, oxidized calmodulin does not efficiently bind calcium/calmodulin-dependent protein kinase II (CaMKII) in rat brain lysates or in vitro. These observations contrast from past experiments performed with oxidized calmodulin and the plasma membrane calcium ATPase, where oxidized calmodulin binds to, and partially activates the PMCA. When taken together, these data suggest that oxidative stress may perturb neuronal and cardiac function via a decreased ability of oxidized calmodulin to bind, activate, and regulate the interactions of CaMKII.
Robison
A J
AJ
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN 37232-0615, USA.
Winder
Danny G
DG
Colbran
Roger J
RJ
Bartlett
Ryan K
RK
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008274:Magnesium / Q000494:pharmacology; D009154:Mutation; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
D002147:Calmodulin; D016194:Receptors, N-Methyl-D-Aspartate; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008274:Magnesium; D002118:Calcium