A simple numerical model of calcium spark formation and detection in cardiac myocytes.
The elementary events of excitation-contraction coupling in heart muscle are Ca2+ sparks, which arise from one or more ryanodine receptors in the sarcoplasmic reticulum (SR). Here a simple numerical model is constructed to explore Ca2+ spark formation, detection, and interpretation in cardiac myocytes. This model includes Ca2+ release, cytosolic diffusion, resequestration by SR Ca2+-ATPases, and the association and dissociation of Ca2+ with endogenous Ca2+-binding sites and a diffusible indicator dye (fluo-3). Simulations in a homogeneous, isotropic cytosol reproduce the brightness and the time course of a typical cardiac Ca2+ spark, but underestimate its spatial size (approximately 1.1 micron vs. approximately 2.0 micron). Back-calculating [Ca2+]i by assuming equilibrium with indicator fails to provide a good estimate of the free Ca2+ concentration even when using blur-free fluorescence data. A parameter sensitivity study reveals that the mobility, kinetics, and concentration of the indicator are essential determinants of the shape of Ca2+ sparks, whereas the stationary buffers and pumps are less influential. Using a geometrically more complex version of the model, we show that the asymmetric shape of Ca2+ sparks is better explained by anisotropic diffusion of Ca2+ ions and indicator dye rather than by subsarcomeric inhomogeneities of the Ca2+ buffer and transport system. In addition, we examine the contribution of off-center confocal sampling to the variance of spark statistics.
Smith
G D
GD
Mathematical Research Branch, National Institutes of Health, Bethesda, Maryland 20814, USA.
Keizer
J E
JE
Stern
M D
MD
Lederer
W J
WJ
Cheng
H
H
D000814:Aniline Compounds; D000818:Animals; D016880:Anisotropy; D055592:Biophysical Phenomena; D001703:Biophysics; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D005456:Fluorescent Dyes; D066298:In Vitro Techniques; D017136:Ion Transport; D007700:Kinetics; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D014966:Xanthenes
D000814:Aniline Compounds; D005456:Fluorescent Dyes; D019837:Ryanodine Receptor Calcium Release Channel; D014966:Xanthenes; C059715:Fluo-3; D000252:Calcium-Transporting ATPases; D002118:Calcium