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

J Biol Chem. 2017 Aug 11;292(32):13361-13373. doi: 10.1074/jbc.M117.781708. Epub 2017 Jun 19.

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.

Keywords: MG23; calcium; excitation-contraction coupling (E-C coupling); heart failure; ion channel; ryanodine receptor; zinc.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abattoirs
  • Animals
  • Calcium Signaling*
  • Cell Hypoxia
  • Cell Line
  • Gene Expression Regulation
  • Lipid Bilayers / metabolism
  • Magnesium / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / isolation & purification
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Patch-Clamp Techniques
  • Permeability
  • Rats
  • Ryanodine Receptor Calcium Release Channel / metabolism*
  • Sarcoplasmic Reticulum / metabolism*
  • Sheep, Domestic
  • Zinc / metabolism*

Substances

  • Lipid Bilayers
  • Membrane Proteins
  • RyR2 protein, rat
  • Ryanodine Receptor Calcium Release Channel
  • mitsugumin23 protein, mouse
  • transmembrane protein 109, rat
  • Magnesium
  • Zinc