Local control models of cardiac excitation-contraction coupling. A possible role for allosteric interactions between ryanodine receptors.
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.
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. sternM@grc.nia.nih.gov
M D
MD
Stern
L S
LS
Song
H
H
Cheng
J S
JS
Sham
H T
HT
Yang
K R
KR
Boheler
E
E
Ríos
D000465:Algorithms; D000818:Animals; D015220:Calcium Channels / Q000502:physiology; D020746:Calcium Channels, L-Type; D003198:Computer Simulation; D004734:Energy Metabolism / Q000502:physiology; D006321:Heart / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008954:Models, Biological; D009010:Monte Carlo Method; D009124:Muscle Proteins / Q000502:physiology; D009200:Myocardial Contraction / Q000502:physiology*; D051381:Rats; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel