Theoretical study of L-type Ca2+ current inactivation kinetics during action potential repolarization and early afterdepolarizations

Stefano Morotti, Eleonora Grandi, Aurora Summa, Kenneth S Ginsburg, Donald M Bers

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Sarcoplasmic reticulum (SR) Ca2+ release mediates excitation-contraction coupling (ECC) in cardiac myocytes. It is triggered upon membrane depolarization by entry of Ca2+ via L-type Ca2+ channels (LTCCs), which undergo both voltage- and Ca2+-dependent inactivation (VDI and CDI, respectively). We developed improved models of L-type Ca2+ current and SR Ca2+ release within the framework of the Shannon-Bers rabbit ventricular action potential (AP) model. The formulation of SR Ca2+ 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. Ba2+ 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 Ca2+ release during the initial AP phase, but by Ca2+ through LTCCs for the remaining part. Simulations of decreased CDI or K+ channel block predicted the occurrence of early and delayed afterdepolarizations. Our model accurately describes ECC and allows dissection of the relative contributions of different Ca2+ sources to total CDI, and the relative roles of CDI and VDI, during normal and abnormal repolarization.

Original languageEnglish (US)
Pages (from-to)4465-4481
Number of pages17
JournalJournal of Physiology
Volume590
Issue number18
DOIs
StatePublished - Sep 2012

ASJC Scopus subject areas

  • Physiology

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