CaMKII autonomy is substrate-dependent and further stimulated by Ca2+/calmodulin

J Biol Chem. 2010 Jun 4;285(23):17930-7. doi: 10.1074/jbc.M109.069351. Epub 2010 Mar 30.


A hallmark feature of Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) regulation is the generation of Ca(2+)-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 ( approximately 70-100%), implicating that it is no longer regulated and that its dramatically increased Ca(2+)/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 Ca(2+)/CaM, both in vitro and within cells. Altered K(m) and V(max) 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 Ca(2+) signals, but prevents complete uncoupling from subsequent cellular stimulation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Animals
  • Calcium / chemistry*
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Calmodulin / chemistry
  • Cell Line
  • Humans
  • Kinetics
  • PC12 Cells
  • Peptides / chemistry
  • Phosphorylation
  • Protein Binding
  • Rats
  • Signal Transduction
  • Substrate Specificity


  • Calmodulin
  • Peptides
  • Adenosine Triphosphate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium