Zinc and sarcoplasmic calcium leak – Paper accepted in JBC

The paper is out!!! Many thanks to the BHF for supporting this work

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) display 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+ (≥2nM) 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.

Here is a link to the paper

http://www.jbc.org/content/early/2017/06/19/jbc.M117.781708.full.pdf?with-ds=yes

European Society of Cardiology Basic Science Summer School in Nice

In June, Amélie Sobczak, PhD student with Dr Alan Stewart, attended the Basic Science Summer School in Nice organised by the European Society of Cardiology. This 5-day event was attended by around 70 PhD and MD/PhD students working in cardiovascular research and consisted of a series of lectures and discussions on the latest advances and challenges in the field as well as workshops on outreach, publishing and career building. During the meeting she presented a poster relating to her research on the regulation of coagulation by zinc, work supported by funding from BHF. She would like to thank the organisers, Jeremy Pearson, Peter Ferdinandy and Yasmine Carrasset. She would also like to thank the School of Medicine and CAPOD for funding to support this visit.

International Society for Zinc Biology 2017

The ISZB meeting 2017 took place in Pyla, Cyprus 18th-22nd June. Samantha Pitt would like to thank for organisers for putting together such an exciting programme.

Samantha gave a talk entitled “Dysregulated zinc may lead to
‘leaky’ calcium channels in heart failure”