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 retic ulum occurs by calcium-induced calcium release through ryanodine receptors (RyRs),which are clustered in a dense, regular, two-dimensional lattice arr ay at the diad junction. We simulated numerically the stochastic dynamics o f 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 ex citation-contraction coupling, due either to insufficiently strong inactiva tion to terminate locally regenerative calcium-induced calcium release or i nsufficient cooperativity to discriminate against RyR activation by backgro und calcium. If the ryanodine receptor was represented, instead, by a pheno menological four-state gating scheme, with channel opening resulting from s imultaneous binding of two Ca2+ ions, and either calcium-dependent or activ ation-linked inactivation, the simulations gave a good semiquantitative acc ounting for the macroscopic features of excitation-con traction coupling. I t was possible to restore stability to a model based on a bilayer-derived g ating scheme, by introducing allosteric interactions between nearest-neighb or RyRs so as to stabilize the inactivated state and produce cooperativity among calcium binding sites on different RyRs. Such allosteric coupling bet ween RyRs may be a function of the foot process and lattice array, explaini ng their conservation during evolution.