Response to Qian and Colvin : zinc-mediated regulation of the cardiac ryanodine receptor occurs via multiple binding sites

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Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release

This work was supported by University of St. Andrews, Tenovus Scotland Grant T14/35 (to S. J. P.), British Heart Foundation Grant FS/14/69/31001 (to S. J. P.), a grant from the John and Lucille van Geest Cardiovascular Diseases Research Fund (to the University of Leicester and R. D. R.), and Biotechnology and Biological Sciences Research Council Grant BB/J006467/1 (to A. J. S.).Aberrant Zn2+-homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force. In this study we addressed whether Zn2+ modulates cardiac ryanodine receptor gating and Ca2+-dynamics in isolated cardiomyocytes. We reveal that Zn2+ is a high affinity regulator of RyR2 displaying three modes of operation. Picomolar free Zn2+ concentrations potentiate RyR2 responses but channel activation is still dependent on the presence of cytosolic Ca2+. At concentrations of free Zn2+ >1 nM, Zn2+ is the main activating ligand and the dependency on Ca2+ is removed. Zn2+ is therefore a higher affinity activator of RyR2 than Ca2+. Millimolar levels of free Zn2+ were found to inhibit channel openings. In cardiomyocytes, consistent with our single-channel results, we show that Zn2+ modulates both the frequency and amplitude of Ca2+ waves in a concentration dependent manner and that physiological levels of Zn2+ elicit Ca2+-release in the absence of activating levels of cytosolic Ca2+. This highlights a new role for intracellular Zn2+ in shaping Ca2+-dynamics in cardiomyocytes through modulation of RyR2 gating.Publisher PDFPeer reviewe

Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release

Aberrant Zn2+-homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force. In this study we addressed whether Zn2+ modulates cardiac ryanodine receptor gating and Ca2+-dynamics in isolated cardiomyocytes. We reveal that Zn2+ is a high affinity regulator of RyR2 displaying three modes of operation. Picomolar free Zn2+ concentrations potentiate RyR2 responses but channel activation is still dependent on the presence of cytosolic Ca2+. At concentrations of free Zn2+ &gt;1 nM, Zn2+ is the main activating ligand and the dependency on Ca2+ is removed. Zn2+ is therefore a higher affinity activator of RyR2 than Ca2+. Millimolar levels of free Zn2+ were found to inhibit channel openings. In cardiomyocytes, consistent with our single-channel results, we show that Zn2+ modulates both the frequency and amplitude of Ca2+ waves in a concentration dependent manner and that physiological levels of Zn2+ elicit Ca2+-release in the absence of activating levels of cytosolic Ca2+. This highlights a new role for intracellular Zn2+ in shaping Ca2+-dynamics in cardiomyocytes through modulation of RyR2 gating.</p