Hierarchical clustering of ryanodine receptors enables emergence of a calcium clock in sinoatrial node cells (original) (raw)
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Interplay of Ryanodine Receptor Distribution and Calcium Dynamics
Biophysical Journal, 2006
Spontaneously generated calcium (Ca 21 ) waves can trigger arrhythmias in ventricular and atrial myocytes. Yet, Ca 21 waves also serve the physiological function of mediating global Ca 21 increase and muscle contraction in atrial myocytes. We examine the factors that influence Ca 21 wave initiation by mathematical modeling and large-scale computational (supercomputer) simulations. An important finding is the existence of a strong coupling between the ryanodine receptor distribution and Ca 21 dynamics. Even modest changes in the ryanodine receptor spacing profoundly affect the probability of Ca 21 wave initiation. As a consequence of this finding, we suggest that there is information flow from the contractile system to the Ca 21 control system and this dynamical interplay could contribute to the increased incidence of arrhythmias during heart failure.
Ryanodine receptor gating controls generation of diastolic calcium waves in cardiac myocytes
The Journal of General Physiology, 2015
The role of cardiac ryanodine receptor (RyR) gating in the initiation and propagation of calcium waves was investigated using a mathematical model comprising a stochastic description of RyR gating and a deterministic description of calcium diffusion and sequestration. We used a one-dimensional array of equidistantly spaced RyR clusters, representing the confocal scanning line, to simulate the formation of calcium sparks. Our model provided an excellent description of the calcium dependence of the frequency of diastolic calcium sparks and of the increased tendency for the production of calcium waves after a decrease in cytosolic calcium buffering. We developed a hypothesis relating changes in the propensity to form calcium waves to changes of RyR gating and tested it by simulation. With a realistic RyR gating model, increased ability of RyR to be activated by Ca2+strongly increased the propensity for generation of calcium waves at low (0.05–0.1-µM) calcium concentrations but only sli...
Journal of General Physiology
The dyads of cardiac myocytes contain ryanodine receptors (RYRs) that generate calcium sparks upon activation. To test how geometric factors of RYR distribution contribute to the formation of calcium sparks, which cannot be addressed experimentally, we performed in silico simulations on a large set of models of calcium release sites (CRSs). Our models covered the observed range of RYR number, density, and spatial arrangement. The calcium release function of CRSs was modeled by RYR openings, with an open probability dependent on concentrations of free Ca2+ and Mg2+ ions, in a rapidly buffered system, with a constant open RYR calcium current. We found that simulations of spontaneous sparks by repeatedly opening one of the RYRs in a CRS produced three different types of calcium release events (CREs) in any of the models. Transformation of simulated CREs into fluorescence signals yielded calcium sparks with characteristics close to the observed ones. CRE occurrence varied broadly with t...
European Biophysics Journal, 2019
Calcium release sites (CRSs) play a key role in excitation-contraction coupling of cardiac myocytes. Recent studies based on electron tomography and super-resolution imaging revealed that CRSs are not completely filled with ryanodine receptors (RyRs) and that the spatial arrangement of RyRs is neither uniform nor static. In this work, we studied the effect of spatial arrangement of RyRs on RyR activation using simulations based on Monte Carlo (MC) and mean-field (MF) approaches. Both approaches showed that activation of RyRs is sensitive to the arrangement of RyRs in the CRS. However, the MF simulations did not reproduce results of MC simulations for non-compact CRSs, suggesting that the approximations used in the MF approach are not suitable for simulation studies of RyRs arrangements observed experimentally. MC simulations revealed the importance of realistic spatial arrangement of RyRs for adequate modelling of calcium release in cardiac myocytes.
Cardiovascular research, 2016
Sino-atrial node (SAN) automaticity is an essential mechanism of heart rate generation that is still not completely understood. Recent studies highlighted the importance of intracellular Ca(2+) ([Ca(2+)]i) dynamics during SAN pacemaker activity. Nevertheless, the functional role of voltage-dependent L-type Ca(2+) channels in controlling SAN [Ca(2+)]i release is largely unexplored. Since Cav1.3 is the predominant L-type Ca(2+) channel isoform in SAN cells, we studied [Ca(2+)]i dynamics in isolated cells and ex vivo SAN preparations explanted from wild-type (WT) and Cav1.3 knockout (KO) mice (Cav1.3(-/-)). We found that Cav1.3 deficiency strongly impaired [Ca(2+)]i dynamics, reducing the frequency of local [Ca(2+)]i release events and preventing their synchronization. This impairment inhibited the generation of Ca(2+) transients and delayed spontaneous activity. We also used action potentials recorded in WT SAN cells as voltage-clamp commands for Cav1.3(-/-)cells. Although these exper...
Cardiac Ca2+ Dynamics: The Roles of Ryanodine Receptor Adaptation and Sarcoplasmic Reticulum Load
Biophysical Journal, 1998
We construct a detailed mathematical model for Ca 2ϩ regulation in the ventricular myocyte that includes novel descriptions of subcellular mechanisms based on recent experimental findings: 1) the Keizer-Levine model for the ryanodine receptor (RyR), which displays adaptation at elevated Ca 2ϩ ; 2) a model for the L-type Ca 2ϩ channel that inactivates by mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca 2ϩ channels empty and interact via Ca 2ϩ . We add membrane currents from the Luo-Rudy Phase II ventricular cell model to our description of Ca 2ϩ handling to formulate a new model for ventricular action potentials and Ca 2ϩ regulation. The model can simulate Ca 2ϩ transients during an action potential similar to those seen experimentally. The subspace [Ca 2ϩ ] rises more rapidly and reaches a higher level (10 -30 M) than the bulk myoplasmic Ca 2ϩ (peak [Ca 2ϩ ] i Ϸ 1 M). Termination of sarcoplasmic reticulum (SR) Ca 2ϩ release is predominately due to emptying of the SR, but is influenced by RyR adaptation. Because force generation is roughly proportional to peak myoplasmic Ca 2ϩ , we use [Ca 2ϩ ] i in the model to explore the effects of pacing rate on force generation. The model reproduces transitions seen in force generation due to changes in pacing that cannot be simulated by previous models. Simulation of such complex phenomena requires an interplay of both RyR adaptation and the degree of SR Ca 2ϩ loading. This model, therefore, shows improved behavior over existing models that lack detailed descriptions of subcellular Ca 2ϩ regulatory mechanisms.
The Journal of General Physiology, 1999
In cardiac muscle, release of activator calcium from the sarcoplasmic reticulum occurs by calcium- induced calcium release through ryanodine receptors (RyRs), which are clustered in a dense, regular, two-dimensional lattice array at the diad junction. We simulated numerically the stochastic dynamics of RyRs and L-type sarcolemmal calcium channels interacting via calcium nano-domains in the junctional cleft. Four putative RyR gating schemes based on single-channel measurements in lipid bilayers all failed to give stable excitation–contraction coupling, due either to insufficiently strong inactivation to terminate locally regenerative calcium-induced calcium release or insufficient cooperativity to discriminate against RyR activation by background calcium. If the ryanodine receptor was represented, instead, by a phenomenological four-state gating scheme, with channel opening resulting from simultaneous binding of two Ca2+ions, and either calcium-dependent or activation-linked inactiva...