Ryanodine Receptor Gating Kinetics in Cardiac Muscle
Catherine
Lloyd
Auckland Bioengineering Institute, The University of Auckland
Model Status
This model runs in OpenCell and COR, and the units are consistent throughout. The current model only describes a single RyR gating scheme, while the paper tests different gating schemes coupled with other dyadic components to recreate ion flows. As these are not described in great depth, this model is likely to remain incomplete and unable to recreate published results. Initial conditions used here are guesses.
Model Structure
ABSTRACT: 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 inactivation, the simulations gave a good semiquantitative accounting for the macroscopic features of excitation-contraction coupling. It was possible to restore stability to a model based on a bilayer-derived gating scheme, by introducing allosteric interactions between nearest-neighbor RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs. Such allosteric coupling between RyRs may be a function of the foot process and lattice array, explaining their conservation during evolution.
The original paper reference is cited below:
Local Control Models of Cardiac Excitation-Contraction Coupling A Possible Role for Allosteric Interactions between Ryanodine Receptors, Michael D. Stern, Long-Sheng Song, Heping Cheng, James S.K. Sham, Huang Tian Yang, Kenneth R. Boheler and Eduardo Rios, 1999, The Journal Of General Physiology, 113, 469-489. PubMed ID: 10051521
Schematic diagram of the RyR models
RyR gating scheme.
calcium dynamics
excitation-contraction coupling
electrophysiology
cardiac myocyte
Cardiac Myocyte
cardic
ryanodine receptor
The University of Auckland, Auckland Bioengineering Institute
Journal of General Physiology
Inactive state
I
Open state
O
Receptor
R
Local Control Models of Cardiac Excitation-Contraction Coupling A Possible Role for Allosteric Interactions between Ryanodine Receptors
113
469
498
Stern et al's 1999 model of a gating scheme for ryanodine receptors.
Cardiac Myocyte
keyword
Catherine
Lloyd
May
The University of Auckland
Auckland Bioengineering Institute
Michael
Stern
D
Eduardo
Rios
This is the CellML description of Stern et al's 1999 model of a gating scheme for ryanodine receptors in cardiac muscle.
c.lloyd@auckland.ac.nz
Long-Sheng
Song
Catherine
Lloyd
May
Catherine Lloyd
2007-05-23T00:00:00+00:00
Huang
Yang
Tian
10051521
Kenneth
Boheler
R
1999-03-01
James
Sham
K
S
2007-06-05T10:46:00+12:00
The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator but gives a flat output.