title: Theoretical study of L-type Ca(2+) current inactivation kinetics during action potential repolarization and early afterdepolarizations.
abstract: Sarcoplasmic reticulum (SR) Ca(2+) release mediates excitation–contraction coupling (ECC) in cardiac myocytes. It is triggered upon membrane depolarization by entry of Ca(2+) via L-type Ca(2+) channels (LTCCs), which undergo both voltage- and Ca(2+)-dependent inactivation (VDI and CDI, respectively). We developed improved models of L-type Ca(2+) current and SR Ca(2+) release within the framework of the Shannon-Bers rabbit ventricular action potential (AP) model. The formulation of SR Ca(2+) release was modified to reproduce high ECC gain at negative membrane voltages. An existing LTCC model was extended to reflect more faithfully contributions of CDI and VDI to total inactivation. Ba(2+) current inactivation included an ion-dependent component (albeit small compared with CDI), in addition to pure VDI. Under physiological conditions (during an AP) LTCC inactivates predominantly via CDI, which is controlled mostly by SR Ca(2+) release during the initial AP phase, but by Ca(2+) through LTCCs for the remaining part. Simulations of decreased CDI or K(+) channel block predicted the occurrence of early and delayed after depolarizations. Our model accurately describes ECC and allows dissection of the relative contributions of different Ca(2+) sources to total CDI, and the relative roles of CDI and VDI, during normal and abnormal repolarization.
authors.affiliation: Department of Pharmacology, University of California, Davis, CA 95616-8636, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Morotti
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
authors.forename: Aurora
authors.initials: A
authors.lastname: Summa
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ginsburg
authors.forename: Donald M
authors.initials: DM
authors.lastname: Bers
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D007700:Kinetics; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000502:physiology; D011817:Rabbits; D015203:Reproducibility of Results; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium