Cardiac Ca2+ Dynamics: The Roles of Ryanodine Receptor Adaptation and Sarcoplasmic Reticulum Load

Cardiac Ca2+ Dynamics: The Roles of Ryanodine Receptor Adaptation and Sarcoplasmic Reticulum Load

Model Status

This model is known to run in both PCEnv and COR, and has been curated by Penny Noble of Oxford University. This variant also contains an embedded CellML description of Niederer, Hunter and Smith's quantitative model of cardiac myocyte regulation. The reference for this paper is given below.

Model Structure

In 1998, M. Saleet Jafri, J. Jeremy Rice and Raimond L. Winslow published a model describing the ventricular action potential. By adding a more sophisticated model of calcium handling, this model builds upon the Di Francesco-Noble and the Luo-Rudy models (see the Luo-Rudy I and the Luo-Rudy II models with their accurate descriptions of membrane currents (see the figure below). Prior to this paper, membrane currents and calcium subsystems had only been considered separately.

The complete original paper reference is cited below:

Cardiac Calcium Dynamics: The Roles of Ryanodine Receptor Adaptation and Sarcoplasmic Reticulum Load, M. Saleet Jafri, J. Jeremy Rice and Raimond L. Winslow, 1998, Biophysical Journal , 74, 1149-1168. (Full text and PDF versions of the article are available for Journal Members on the Biophysical Journal website.) PubMed ID: 9512016

ABSTRACT

We construct a detailed mathematical model for Ca2+ 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 Ca2+; 2) a model for the L-type Ca2+ channel that inactivates by mode switching; and 3) a restricted subspace into which the RyRs and L-type Ca2+ channels empty and interact via Ca2+. We add membrane currents from the Luo-Rudy Phase II ventricular cell model to our description of Ca2+ handling to formulate a new model for ventricular action potentials and Ca2+ regulation. The model can simulate Ca2+ transients during an action potential similar to those seen experimentally. The subspace [Ca2+] rises more rapidly and reaches a higher level (10-30 µM) than the bulk myoplasmic Ca2+ (peak [Ca2+]i approx 1 µM). Termination of sarcoplasmic reticulum (SR) Ca2+ release is predominately due to emptying of the SR, but is influenced by RyR adaptation. Because force generation is roughly proportional to peak myoplasmic Ca2+, we use [Ca2+]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 Ca2+ loading. This model, therefore, shows improved behavior over existing models that lack detailed descriptions of subcellular Ca2+ regulatory mechanisms.

The reference for the embedded Niederer Hunter Smith model of cardiac myocyte relaxation is: "A Quantitative Analysis of Cardiac Myocyte Relaxation: A Simulation Study" Niederer, S.A., Hunter, P.J., Smith, N.P, Biophysical Journal, Volume 90, March 2006, pp. 1697-1722.

The raw CellML description of the Jafri-Rice-Winslow model can be downloaded in various formats as described in . For an example of a more complete documentation for an electrophysiological model, see The Hodgkin-Huxley Squid Axon Model, 1952.

A schematic diagram describing the current flows across the cell membrane that are captured in the Jafri-Rice-Winslow model.
The network defined in the CellML description of the Jafri-Rice-Winslow model. A key describing the significance of the shapes of the components and the colours of the connections between them is in the notation guide. For simplicity, not all the variables are shown.

The membrane physically contains the currents, exchangers and pumps, as indicated by the blue arrows in . The currents act independently and are not connected to each other. Several of the channels encapsulate and contain further components which represent activation and inactivation gates. The addition of an encapsulation relationship informs modellers and processing software that the gates are important parts of the current model. It also prevents any other components that aren't also encapsulated by the parent component from connecting to its gates, effectively hiding them from the rest of the model.

The breakdown of the model into components and the definition of encapsulation and containment relationships between them is somewhat arbitrary. When considering how a model should be broken into components, modellers are encouraged to consider which parts of a model might be re-used and how the physiological elements of the system being modelled are naturally bounded. Containment relationships should be used to provide simple rendering information for processing software (ideally, this will correspond to the layout of the physical system), and encapsulation should be used to group sets of components into sub-models.