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

• Published in: Biophysical journal Vol. 104; no. 10; pp. 2149 - 2159
• Main Authors: Cannell, M.B., Kong, C.H.T., Imtiaz, M.S., Laver, D.R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.05.2013; The Biophysical Society
• 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
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/j.bpj.2013.03.058

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.