Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release

Abstract

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.