Abstract
Frequency-dependent acceleration of relaxation (FDAR) of both Ca2+ transient and twitch contraction is a pivotal mechanism for regulating cardiac contraction. The Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been suggested to be involved in the FDAR. So far several computer models were developed to examine how CaMKII activity is regulated by heart rate, but these were not directly based on experimental data of the cardiac isoform, CaMKIIδ or did not consider deactivation of CaMKII by phosphatases (PPs). To advance our understanding of the significance of CaMKII autophosphorylation and its regulation by PPs in heart, we developed a new mathematical model for CaMKIIδ. Since more experimental data were available for the neuronal CaMKIIα isoform, the model was first adjusted for the α isoform and then fitted to kinetic data of the δ isoform, which has a higher affinity for calmodulin and a higher autophosphorylation rate. Our simulation demonstrated that repetitive Ca2+ transients cumulatively increased a fraction of autophosphorylated CaMKIIδ in a manner dependent on beating frequency. Variation in the PP activity was capable of modifying the CaMKIIδ activation level. These simulation results indicated that CaMKIIδ is cumulatively activated within a physiological range of heart rate and the PP activity effectively modulates the CaMKIIδ activity. [J Physiol Sci. 2008;58 Suppl:S46]
