Journal
JOURNAL OF GENERAL PHYSIOLOGY
Volume 140, Issue 2, Pages 93-108Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1085/jgp.201110708
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Funding
- European Union [LSHM-CT-2005-018802/CONTICA, LSHM-CT-2005-018833/EUGeneHeart]
- Slovak Scientific Grant Agency [VEGA 2/0033/11, 2/0190/10]
- Slovak Research and Development Agency [APVV-0139-06, APVV-0721-10, APVV-SK-CZ-0172-09]
- Research and Development Operational Program
- European Regional Development Fund
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The synergic effect of luminal Ca2+, cytosolic Ca2+, and cytosolic adenosine triphosphate (ATP) on activation of cardiac ryanodine receptor (RYR2) channels was examined in planar lipid bilayers. The dose-response of RYR2 gating activity to ATP was characterized at a diastolic cytosolic Ca2+ concentration of 100 nM over a range of luminal Ca2+ concentrations and, vice versa, at a diastolic luminal Ca2+ concentration of 1 mM over a range of cytosolic Ca2+ concentrations. Low level of luminal Ca2+ (1 mM) significantly increased the affinity of the RYR2 channel for ATP but without substantial activation of the channel. Higher levels of luminal Ca2+ (8-53 mM) markedly amplified the effects of ATP on the RYR2 activity by selectively increasing the maximal RYR2 activation by ATP, without affecting the affinity of the channel to ATP. Near-diastolic cytosolic Ca2+ levels (<500 nM) greatly amplified the effects of luminal Ca2+. Fractional inhibition by cytosolic Mg2+ was not affected by luminal Ca2+. In models, the effects of luminal and cytosolic Ca2+ could be explained by modulation of the allosteric effect of ATP on the RYR2 channel. Our results suggest that luminal Ca2+ ions potentiate the RYR2 gating activity in the presence of ATP predominantly by binding to a luminal site with an apparent affinity in the millimolar range, over which local luminal Ca2+ likely varies in cardiac myocytes.
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