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Although the highly conserved Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is known to play an essential role in cardiac myocytes, its involvement in the frequency-dependent acceleration of relaxation is still controversial. To investigate the functional significance of CaMKII autophosphorylation and its regulation by protein phosphatases (PPs) in heart, we developed a new mathematical model for the CaMKIIdelta isoform. Due to better availability of experimental data, the model was first adjusted to the kinetics of the neuronal CaMKIIalpha isoform and then converted to a CaMKIIdelta model by fitting to kinetic data of the delta isoform. Both models satisfactorily reproduced experimental data of the CaMKII-calmodulin interaction, the autophosphorylation rate, and the frequency dependence of activation. The level of autophosphorylated CaMKII cumulatively increased upon starting the Ca(2+) stimulation at 3 Hz in the delta model. Variations in PP concentration remarkably affected the frequency-dependent activation of CaMKIIdelta, suggesting that cellular PP activity plays a key role in adjusting CaMKII activation in heart. The inhibitory effect of PP was stronger for CaMKIIalpha compared to CaMKIIdelta. Simulation results revealed a potential involvement of CaMKIIdelta autophosphorylation in the frequency-dependent acceleration of relaxation at physiological heart rates and PP concentrations.