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⁺ >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.