Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release *

摘要

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. 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 n m , 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.