CaMKII Autonomy Is Substrate-dependent and Further Stimulated by Ca2+/Calmodulin

A hallmark feature of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) regulation is the generation of Ca2+-independent autonomous activity by Thr-286 autophosphorylation. CaMKII autonomy has been regarded a form of molecular memory and is indeed important in neuronal plasticity and learni...

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Published in:The Journal of biological chemistry 2010-06, Vol.285 (23), p.17930-17937
Main Authors: Coultrap, Steven J., Buard, Isabelle, Kulbe, Jaqueline R., Dell'Acqua, Mark L., Bayer, K. Ulrich
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Animals
Calcium
Calcium - chemistry
Calcium - metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Calcium/Calmodulin
Calmodulin - chemistry
Cell Line
Enzymes/Kinase
Humans
Kinetics
Neurobiology
Neurobiology/Neuroscience
PC12 Cells
Peptides - chemistry
Phosphorylation
Protein Binding
Rats
Signal Transduction
Signal Transduction/Protein Kinases/Calmodulin
Signal Transduction/Protein Kinases/Serine/Threonine
Substrate Specificity
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Summary:A hallmark feature of Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) regulation is the generation of Ca2+-independent autonomous activity by Thr-286 autophosphorylation. CaMKII autonomy has been regarded a form of molecular memory and is indeed important in neuronal plasticity and learning/memory. Thr-286-phosphorylated CaMKII is thought to be essentially fully active (∼70–100%), implicating that it is no longer regulated and that its dramatically increased Ca2+/CaM affinity is of minor functional importance. However, this study shows that autonomy greater than 15–25% was the exception, not the rule, and required a special mechanism (T-site binding; by the T-substrates AC2 or NR2B). Autonomous activity toward regular R-substrates (including tyrosine hydroxylase and GluR1) was significantly further stimulated by Ca2+/CaM, both in vitro and within cells. Altered Km and Vmax made autonomy also substrate- (and ATP) concentration-dependent, but only over a narrow range, with remarkable stability at physiological concentrations. Such regulation still allows molecular memory of previous Ca2+ signals, but prevents complete uncoupling from subsequent cellular stimulation.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.069351