Zusammenfassung
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.
Nutzer