title: Modulatory effect of calmodulin-dependent kinase II (CaMKII) on sarcoplasmic reticulum Ca2+ handling and interval-force relations: a modelling study.
abstract: We hypothesize that slow inactivation of Ca2+/calmodulin-dependent kinase II (CaMKII) and its modulatory effect on sarcoplasmic reticulum (SR) Ca2+ handling are important for various interval-force (I-F) relations, in particular for the beat interval dependency in transient alternans during the decay of post-extrasystolic potentiation. We have developed a mathematical model of a single cardiomyocyte to integrate various I-F relations, including alternans, by incorporating a conceptual CaMKII kinetics model into the SR Ca2+ handling model. Our model integrates I-F relations, such as the beat interval-dependent twitch force duration, restitution and potentiation, positive staircase phenomenon and alternans. We found that CaMKII affects more or less all I-F relations, and it is a key factor for integration of the various I-F relations in our model. Alternans arises, in the model, out of a steep relation between SR Ca2+ load and release, owing to SR load-dependent changes in the releasability of Ca2+ via the ryanodine receptor. Beat interval-dependent CaMKII activity, owing to its kinetic properties and amplifying effect on SR Ca2+ load dependency of Ca2+ release, replicated the beat interval dependency of alternans, as observed experimentally. Additionally, our model enabled reproduction of the effects of various interventions on alternans, such as the slowing or accelerating of Ca2+ release and/or uptake. We conclude that a slow time-dependent factor, represented in the model by CaMKII, is important for the integration of I-F relations, including alternans, and that our model offers a useful tool for further analysis of the roles of integrative Ca2+ handling in myocardial I-F relations.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK. gentaro.iribe@physiol.ox.ac.uk
authors.forename: Gentaro
authors.initials: G
authors.lastname: Iribe
authors.forename: Peter
authors.initials: P
authors.lastname: Kohl
authors.forename: Denis
authors.initials: D
authors.lastname: Noble
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003198:Computer Simulation; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium