Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release.

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 dependency 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.