Transient versus asymptotic dynamics of CaM kinase II: Possible roles of phosphatase

Calmodulin-dependent protein kinase II (CaMKII) is known to play a key role during induction of long-term potentiation (LTP). Given the dependence of LTP on the frequency of synaptic activation, several previous modeling efforts have proposed that biochemical properties of CaMKII itself might be in part responsible for this dependence. Recently, De Koninck and Schulman (1998) have provided direct experimental evidence that the enzyme itself is sensitive to the frequency of Ca2+ activation. Here we demonstrate the ability of a detailed biophysical model constructed solely on enzyme kinetics of purified proteins to generate the frequency sensitivity demonstrated by De Koninck and Schulman. Quantitative analysis of the model reveals that this frequency sensitivity is provided by a mechanism different from those previously postulated. This analysis leads to specific predictions concerning the effects of mutations on this process. We further employ the model to examine the asymptotic behavior of CaMKII-phosphatase system during longer simulated periods of stimulation. The analyses of the model suggest that the transient and asymptotic frequency sensitivity of this enzyme are dependent on different biochemical mechanisms. These results may be applicable to Ca2+/calmodulin signaling pathways in general.