Control of Sarcoplasmic Reticulum Ca2+ Release by Stochastic RyR Gating within a 3D Model of the Cardiac Dyad and Importance of Induction Decay for CICR Termination

The factors responsible for the regulation of regenerative calcium-induced calcium release (CICR) during Ca2+ spark evolution remain unclear. Cardiac ryanodine receptor (RyR) gating in rats and sheep was recorded at physiological Ca2+, Mg2+, and ATP levels and incorporated into a 3D model of the car...

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Bibliographic Details
Published in:Biophysical journal 2013-05, Vol.104 (10), p.2149-2159
Main Authors: Cannell, M.B., Kong, C.H.T., Imtiaz, M.S., Laver, D.R.
Format: Article
Language:English
Subjects:
adenosine triphosphate
Animals
ATP
calcium
Calcium - metabolism
Calcium Signaling
Cell Biophysics
Ion Channel Gating
magnesium
Models, Biological
Myocardium - metabolism
Myocardium - ultrastructure
Rats
Rats, Sprague-Dawley
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcolemma - metabolism
Sarcolemma - ultrastructure
sarcoplasmic reticulum
Sarcoplasmic Reticulum - metabolism
Sarcoplasmic Reticulum - physiology
Sarcoplasmic Reticulum - ultrastructure
sheep
Stochastic Processes
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Summary:The factors responsible for the regulation of regenerative calcium-induced calcium release (CICR) during Ca2+ spark evolution remain unclear. Cardiac ryanodine receptor (RyR) gating in rats and sheep was recorded at physiological Ca2+, Mg2+, and ATP levels and incorporated into a 3D model of the cardiac dyad, which reproduced the time course of Ca2+ sparks, Ca2+ blinks, and Ca2+ spark restitution. The termination of CICR by induction decay in the model principally arose from the steep Ca2+ dependence of RyR closed time, with the measured sarcoplasmic reticulum (SR) lumen Ca2+ dependence of RyR gating making almost no contribution. The start of CICR termination was strongly dependent on the extent of local depletion of junctional SR Ca2+, as well as the time course of local Ca2+ gradients within the junctional space. Reducing the dimensions of the dyad junction reduced Ca2+ spark amplitude by reducing the strength of regenerative feedback within CICR. A refractory period for Ca2+ spark initiation and subsequent Ca2+ spark amplitude restitution arose from 1), the extent to which the regenerative phase of CICR can be supported by the partially depleted junctional SR, and 2), the availability of releasable Ca2+ in the junctional SR. The physical organization of RyRs within the junctional space had minimal effects on Ca2+ spark amplitude when more than nine RyRs were present. Spark amplitude had a nonlinear dependence on RyR single-channel Ca2+ flux, and was approximately halved by reducing the flux from 0.6 to 0.2 pA. Although rat and sheep RyRs had quite different Ca2+ sensitivities, Ca2+ spark amplitude was hardly affected. This suggests that moderate changes in RyR gating by second-messenger systems will principally alter the spatiotemporal properties of SR release, with smaller effects on the amount released.
ISSN:0006-3495
1542-0086
DOI:10.1016/j.bpj.2013.03.058