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.

SUBMITTER: Reilly-O'Donnell B 

PROVIDER: S-EPMC5555195 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature