Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release*

Abstract

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.

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 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.