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, Eduardo Ríos

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)469-489
Number of pages21
JournalJournal of General Physiology
Volume113
Issue number3
DOIs
StatePublished - Mar 1999

Keywords

  • Calcium-induced calcium release
  • Diad junction
  • Dihydropyridine receptor
  • Monte Carlo
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • Physiology

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