A 3D Monte Carlo Analysis of the Role of Dyadic Space Geometry in Spark Generation

Abstract

In multiple biological systems, vital intracellular signaling processes occur locally in minute periplasmic subspaces often referred to as signaling microdomains. The number of signaling molecules in these microdomains is small enough to render the notion of continuous concentration changes invalid, such that signaling events are better described using stochastic rather than deterministic methods. Of particular interest is the dyadic cleft in the cardiac myocyte, where short-lived, local increases in intracellular Ca2+ known as Ca2+ sparks regulate excitation-contraction coupling. The geometry of dyadic spaces can alter in disease and development and display significant interspecies variability. We created and studied a 3D Monte Carlo model of the dyadic cleft, specifying the spatial localization of L-type Ca2+ channels and ryanodine receptors. Our analysis revealed how reaction specificity and efficiency are regulated by microdomain geometry as well as the physical separation of signaling molecules into functional complexes. The spark amplitude and rise time were found to be highly dependent on the concentration of activated channels per dyadic cleft and on the intermembrane separation, but not very sensitive to other cleft dimensions. The role of L-type Ca2+ channel and ryanodine receptor phosphorylation was also examined. We anticipate that this modeling approach may be applied to other systems (e.g., neuronal growth cones and chemotactic cells) to create a general description of stochastic events in Ca2+ signaling.

Ryanodine Receptor-Mediated Ca²⁺ Events in Atrial Myocytes of Patients with Atrial Fibrillation

“…Third, although no difference was found in cell morphology between the AF and NSR groups, the ultrastructure of the gap between the sarcolemma and SR membrane was not investigated in this study. Since the structure of the gap region is critical in shaping Ca 2+ sparks [19, 23], the possibility that structural remodeling of the gap region in AF atrial myocytes is responsible for the reshaping of Ca 2+ sparks cannot be excluded. Finally, because the LAD of AF patients was significantly larger than that of NSR patients (table 1), it is possible that the altered Ca 2+ sparks can be accounted for by the LAD difference.…”

EFFICIENT AND DETAILED MODEL OF THE LOCAL Ca2+ RELEASE UNIT IN THE VENTRICULAR CARDIAC MYOCYTE

“…The channel gating and the flux through open channels is treated stochastically. A similar approch was presented in Koh et al [11]. Nevertheless this models are very time expensive and not suitable for whole cell simulations.…”

Microstructure-Based Monte Carlo Simulation of Ca2+ Dynamics Evoking Cardiac Calcium Channel Inactivation

“…Each agent may change its state, spatial position, and posture with time according to its own rules. This in silico platform was validated, for example, by confi rming the reproduction ability for a similar Monte Carlo simulation on Ca 2+ dynamics in the dyadic space performed by Koh et al [27] (Kawazu et al [33]). Our simulations of the Ca 2+ dynamics in the heart cell employed an agent-based model that includes LCCs, individual Ca 2+ ions, surface membrane, and JSR membrane surface with RyRs as the agents.…”

“…LCC-RyR signaling in them was influenced by both the stochastic dynamics of Ca 2+ in the dyad as well as by the shape and relative positioning of the different proteins in the dyad. Here we construct microstructure-based models whose geometry is similar to what Koh et al [27] and Tanskanen et al [26] presented. Our model used in the current study is much simpler than the one by Tanskanen et al [26] because it does not include calmodulin (CaM) or a CICR mechanism.…”

“…The Monte Carlo method has begun to be used to examine Ca 2+ dynamics in the dyadic space. For example, Koh et al [27] and Tanskanen et al [26] developed models of stochastic molecular signaling between LCCs and RyR. LCC-RyR signaling in them was influenced by both the stochastic dynamics of Ca 2+ in the dyad as well as by the shape and relative positioning of the different proteins in the dyad.…”