Modelling cardiac calcium sparks in a three-dimensional reconstruction of a calcium release unit

Johan Hake, Andrew G. Edwards, Zeyun Yu, Peter M. Kekenes-Huskey, Anushka P. Michailova, J. Andrew Mccammon, Michael J. Holst, Masahiko Hoshijima, Andrew D. Mcculloch

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca2+ release unit (CRU) is the fundamental event of cardiac excitation-contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca2+ leak in cardiomyocytes. Previous model studies have predicted that the duration and magnitude of the spark is determined by the local CRU geometry, as well as the localization and density of Ca2+ handling proteins. We have created a detailed computational model of a CRU, and developed novel tools to generate the computational geometry from electron tomographic images. Ca2+ diffusion was modelled within the SR and the cytosol to examine the effects of localization and density of the Na+/Ca2+ exchanger, sarco/endoplasmic reticulum Ca2+-ATPase 2 (SERCA), and calsequestrin on spark dynamics. We reconcile previous model predictions of approximately 90% local Ca2+ depletion in junctional SR, with experimental reports of about 40%. This analysis supports the hypothesis that dye kinetics and optical averaging effects can have a significant impact on measures of spark dynamics. Our model also predicts that distributing calsequestrin within non-junctional Z-disc SR compartments, in addition to the junctional compartment, prolongs spark release time as reported by Fluo5. By pumping Ca2+ back into the SR during a release, SERCA is able to prolong a Ca2+ spark, and this may contribute to SERCA-dependent changes in Ca2+ wave speed. Finally, we show that including the Na+/Ca2+ exchanger inside the dyadic cleft does not alter local [Ca2+] during a spark.

Original languageEnglish (US)
Pages (from-to)4403-4422
Number of pages20
JournalJournal of Physiology
Volume590
Issue number18
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

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    Hake, J., Edwards, A. G., Yu, Z., Kekenes-Huskey, P. M., Michailova, A. P., Mccammon, J. A., Holst, M. J., Hoshijima, M., & Mcculloch, A. D. (2012). Modelling cardiac calcium sparks in a three-dimensional reconstruction of a calcium release unit. Journal of Physiology, 590(18), 4403-4422. https://doi.org/10.1113/jphysiol.2012.227926