A simulation study on the activation of cardiac CaMKII δ-isoform and its regulation by phosphatases

Although the highly conserved Ca2+/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 CaMKII delta isoform. Due to better availability of experimental data, the model was first adjusted to the kinetics of the neuronal CaMKII alpha isoform and then converted to a CaMKIId 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 Ca2+ stimulation at 3 Hz in the delta model. Variations in PP concentration remarkably affected the frequency-dependent activation of CaMKIId, suggesting that cellular PP activity plays a key role in adjusting CaMKII activation in heart. The inhibitory effect of PP was stronger for CaMKIIa compared to CaMKIId. Simulation results revealed a potential involvement of CaMKIId autophosphorylation in the frequency-dependent acceleration of relaxation at physiological heart rates and PP concentrations.