title: Intracellular Zinc Modulates Cardiac Ryanodine Receptor-mediated Calcium Release.
abstract: 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 dependence 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.
authors.affiliation: From the School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, United Kingdom and.
authors.forename: Jason
authors.initials: J
authors.lastname: Woodier
authors.affiliation: the Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield General Hospital, Leicester LE3 9QP, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Rainbow
authors.affiliation: From the School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, United Kingdom and.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Stewart
authors.affiliation: From the School of Medicine, University of St. Andrews, St. Andrews KY16 9TF, United Kingdom and sjp24@st-andrews.ac.uk.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Pitt
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D003600:Cytosol / Q000378:metabolism; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D008297:Male; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D034561:Sheep, Domestic; D015032:Zinc / Q000378:metabolism*
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D015032:Zinc
keywords: calcium; excitation-contraction coupling (E-C coupling); heart failure; ryanodine receptor; zinc