CaMKII autonomy is substrate-dependent and further stimulated by Ca2+/calmodulin.
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.
Coultrap
Steven J
SJ
Department of Pharmacology, University of Colorado Denver School of Medicine, Aurora, Colorado 80045, USA.
Buard
Isabelle
I
Kulbe
Jaqueline R
JR
Dell'Acqua
Mark L
ML
Bayer
K Ulrich
KU
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002147:Calmodulin / Q000737:chemistry; D002460:Cell Line; D006801:Humans; D007700:Kinetics; D016716:PC12 Cells; D010455:Peptides / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D013379:Substrate Specificity
D002147:Calmodulin; D010455:Peptides; D000255:Adenosine Triphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium