Diketopyridylryanodine has three concentration-dependent effects on the cardiac calcium-release channel/ryanodine receptor

Keshore R. Bidasee, Le Xu, Gerhard Meissner, Henry R. Besch

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


By interacting with more than one site, ryanoids induce multiple effects on calcium-release channels. To date, the kinetics of interaction of only one of these sites has been characterized. Using C4, C12-diketopyridylryanodine in both [3H]ryanodine binding and single channel experiments we characterized another site on the cardiac ryanodine receptor (RyR2) with which ryanoids interact. Competitive binding of this ryanoid to RyR2 implied a minimal two-site binding model. At the single channel level, C4, C12-diketopyridylryanodine induced three distinct effects. At nanomolar concentrations, it increased channel open probability severalfold without inducing a subconductance. This effect was independent of membrane holding potential. As for other ryanoids, low micromolar concentrations of C4, C12-diketopyridylryanodine readily induced a subconductance state. The major subconductance had a current amplitude of 52% of fully open, it was reversible, and its time to induction and duration were voltage- and concentration-dependent, affording Hill slopes of >2. At higher micromolar concentrations C4,C12-diketopyridylryanodine induced long lasting, yet reversible shut states. Using a pharmacological strategy we have discerned an additional ryanoid-binding site on RyR2 that triggers an increase in channel activity. This site likely resides outside the strict confines of the transmembrane conducting pathway.

Original languageEnglish (US)
Pages (from-to)14237-14248
Number of pages12
JournalJournal of Biological Chemistry
Issue number16
StatePublished - Apr 18 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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