Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release

Abstract

Aberrant Zn 2+ homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force. In this study, we addressed whether Zn 2+ modulates cardiac ryanodine receptor gating and Ca 2+ dynamics in isolated cardiomyocytes. We reveal that Zn 2+ is a high affinity regulator of RyR2 displaying three modes of operation. Picomolar free Zn 2+ concentrations potentiate RyR2 responses, but channel activation is still dependent on the presence of cytosolic Ca 2+ . At concentrations of free Zn 2+ >1 nm, Zn 2+ is the main activating ligand, and the dependence on Ca 2+ is removed. Zn 2+ is therefore a higher affinity activator of RyR2 than Ca 2+ . Millimolar levels of free Zn 2+ were found to inhibit channel openings. In cardiomyocytes, consistent with our single channel results, we show that Zn 2+ modulates both the frequency and amplitude of Ca 2+ waves in a concentration-dependent manner and that physiological levels of Zn 2+ elicit Ca 2+ release in the absence of activating levels of cytosolic Ca 2+ . This highlights a new role for intracellular Zn 2+ in shaping Ca 2+ dynamics in cardiomyocytes through modulation of RyR2 gating. Background: In heart failure, the release of calcium becomes erratic leading to the generation of arrhythmias. Dysregulated Zn 2+ homeostasis occurs in chronic heart failure. Results: Zn 2+ can directly activate RyR2, removing the dependence of Ca 2+ for channel activation. Conclusion: Zn 2+ shapes Ca 2+ dynamics by directly interacting with and modulating RyR2 function. Significance: This highlights a new role for Zn 2+ in cardiac excitation-contraction coupling.