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.
Highlights
In heart failure, the release of calcium becomes erratic leading to the generation of arrhythmias
We addressed whether Zn2؉ modulates cardiac ryanodine receptor gating and Ca2؉ dynamics in isolated cardiomyocytes
When Zn2ϩ levels were incremented in a cumulative fashion, channel activation plateaued at 1 nM Zn2ϩ, and higher concentrations of Zn2ϩ (Ͼ10 nM) had no further significant effect on channel Po (Fig. 1B)
Summary
The release of calcium becomes erratic leading to the generation of arrhythmias. 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. Aberrant Zn2ϩ homeostasis has been shown to be associated with cardiomyopathy including chronic heart failure, and myocardial damage as a result of dysregulated intracellular Ca2ϩ release, reduced cardiac contractility, and significantly prolonged rises of systolic Ca2ϩ (16 –19). We show that Zn2ϩ is a potent regulator of SR Ca2ϩ release through modulation of RyR2 channel function and that Zn2ϩ plays a key role in shaping intracellular Ca2ϩ dynamics important in cardiac excitation-contraction coupling
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