Intracellular zinc modulates cardiac ryanodine receptor-mediated calcium release.
journal contributionposted on 2015-07-16, 15:56 authored by J. Woodier, Richard D. Rainbow, A. J. Stewart, S. J. Pitt
Aberrant Zn(2+)-homeostasis is a hallmark of certain cardiomyopathies associated with altered contractile force. In this study we addressed whether Zn(2+) modulates cardiac ryanodine receptor gating and Ca(2+)-dynamics in isolated cardiomyocytes. We reveal that Zn(2+) is a high affinity regulator of RyR2 displaying three modes of operation. Picomolar free Zn(2+) concentrations potentiate RyR2 responses but channel activation is still dependent on the presence of cytosolic Ca(2+). At concentrations of free Zn(2+) >1 nM, Zn(2+) is the main activating ligand and the dependency on Ca(2+) is removed. Zn(2+) is therefore a higher affinity activator of RyR2 than Ca(2+). Millimolar levels of free Zn(2+) were found to inhibit channel openings. In cardiomyocytes, consistent with our single-channel results, we show that Zn(2+) modulates both the frequency and amplitude of Ca(2+) waves in a concentration dependent manner and that physiological levels of Zn(2+) elicit Ca(2+)-release in the absence of activating levels of cytosolic Ca(2+). This highlights a new role for intracellular Zn(2+) in shaping Ca(2+)-dynamics in cardiomyocytes through modulation of RyR2 gating.
This work was supported by University of St. Andrews, Tenovus Scotland Grant T14/35 (to S. J. P.), British Heart Foundation Grant FS/14/69/31001 (to S. J. P.), a grant from the John and Lucille van Geest Cardiovascular Diseases Research Fund (to the University of Leicester and R. D. R.), and Biotechnology and Biological Sciences Research Council Grant BB/J006467/1 (to A. J. S.).
CitationThe Journal of Biological Chemistry, Vol. 290, No. 28, pp. 17599 –17610, July 10, 2015
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences
- VoR (Version of Record)