Sensitivity of CaM kinase II to the frequency of Ca 2+ oscillations: a simple model

Abstract

The rules that govern the activation and autophosphorylation of the multifunctional Ca 2+–calmodulin kinase II (CaMKII) by Ca 2+ and calmodulin (CaM) are thought to underlie its ability to decode Ca 2+ oscillations and to control multiple cellular functions. We propose a simple biophysical model for the activation of CaMKII by Ca 2+ and calmodulin. The model describes the transition of the subunits of the kinase between their different possible states (inactive, bound to Ca 2+–CaM, phosphorylated at Thr 286, trapped and autonomous). All transitions are described by classical kinetic equations except for the autophosphorylation step, which is modeled in an empirical manner. The model quantitatively reproduces the experimentally demonstrated frequency sensitivity of CaMKII [Science 279 (1998) 227]. We further use the model to investigate the role of several characterized features of the kinase—as well as some that are not easily attainable by experiments—in its frequency-dependent responses. In cellular microdomains, CaMKII is expected to sense very brief Ca 2+ spikes; our simulations under such conditions reveal that the enzyme response is tuned to optimal frequencies. This prediction is then confirmed by experimental data. This novel and simple model should help in understanding the rules that govern CaMKII regulation, as well as those involved in decoding intracellular Ca 2+ signals.