Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage

Abstract

Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (≥2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+. Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage.

The redox biology of redox-inert zinc ions

“…Indeed, zinc deficiency in animals depresses Ca 2+ -ATPase activity in erythrocyte membranes [125]. Also, an increase of cellular "free" zinc ions to concentration >2 nM, as observed in ischemia, leads to calcium leakage from the cardiac redox-sensitive ryanodine receptor/calcium channel (RyR2) [126]. The increase of cellular calcium activates NADPH oxidase and NOS and results in the production of reactive species.…”

Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease

“…Zn is proposed as an intracellular second messenger (for reviews, see: [ 124 , 125 ]). Zn is a direct caspase cofactor in the regulation of the apoptotic cascade [ 126 ], and has been implicated in neurotransmitter regulation [ 127 , 128 , 129 ] and in cardiomyocyte function through the regulation of ryanodine receptor 2 (RyR2) [ 130 , 131 ]. A crucial cofactor, Zn is integral to the function of over 300 enzymes throughout all six classes (i.e., oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases) [ 132 ].…”

Zinc in Wound Healing Modulation

“…The zinc transporter protein (ZIP) family zinc uptake/transporter proteins, particularly ZIP4, are responsible for zinc uptake from the extracellular milieu or intracellular vesicles [ 15 ]. Cytosolic free zinc ions have recently been identified as secondary messengers, similar to calcium ion transients, capable of interacting with target proteins in order to regulate many signal transduction pathways [ 16 , 17 ]. In this regard, zinc availability and regulation constitute an important component in cell physiology.…”