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J. Biol. Chem., Vol. 278, Issue 16, 14237-14248, April 18, 2003

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Diketopyridylryanodine Has Three Concentration-dependent Effects on the Cardiac Calcium-release Channel/Ryanodine Receptor^*

Keshore R. Bidasee^§¶, Le Xu^§, Gerhard Meissner, and Henry R. Besch Jr.^**

From the  Department of Pharmacology, University of Nebraska Medical Center, Omaha, Nebraska 68198, the  Departments of Biochemistry and Biophysics and Cell and Molecular Physiology, University of North Carolina, Chapel Hill, North Carolina 27599-7260, and the ^** Departments of Pharmacology and Medicine and Krannert Institute of Cardiology, Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202

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.

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