title: Modelling cardiac calcium sparks in a three-dimensional reconstruction of a calcium release unit.
abstract: Triggered release of Ca2+ from an individual sarcoplasmic reticulum (SR) Ca(2+) release unit (CRU) is the fundamental event of cardiac excitation–contraction coupling, and spontaneous release events (sparks) are the major contributor to diastolic Ca(2+) 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 Ca(2+) 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. Ca(2+) diffusion was modelled within the SR and the cytosol to examine the effects of localization and density of the Na(+)/Ca(2+) exchanger, sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA), and calsequestrin on spark dynamics. We reconcile previous model predictions of approximately 90% local Ca(2+) 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 Ca(2+) back into the SR during a release, SERCA is able to prolong a Ca(2+) spark, and this may contribute to SERCA-dependent changes in Ca(2+) wave speed. Finally, we show that including the Na(+)/Ca(2+) exchanger inside the dyadic cleft does not alter local [Ca(2+)] during a spark.
authors.affiliation: Department of Bioengineering, University of California San Diego, CA, USA. johan.hake@gmail.com
authors.forename: Johan
authors.initials: J
authors.lastname: Hake
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Edwards
authors.forename: Zeyun
authors.initials: Z
authors.lastname: Yu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Kekenes-Huskey
authors.forename: Anushka P
authors.initials: AP
authors.lastname: Michailova
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Holst
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Andrew D
authors.initials: AD
authors.lastname: McCulloch
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D051379:Mice; D008955:Models, Cardiovascular; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium