- Title
- Differences in the regulation of RyR2 from human, sheep, and rat by Ca²⁺ and Mg²⁺ in the cytoplasm and in the lumen of the sarcoplasmic reticulum
- Creator
- Walweel, Kafa; Li, Jiao; Molenaar, Peter; Imtiaz, Mohammad S.; Quail, Anthony; dos Remedios, Chris G.; Beard, Nicole A.; Dulhunty, Angela F.; van Helden, Dirk F.; Laver, Derek R.
- Relation
- NHMRC.631052
- Relation
- Journal of General Physiology Vol. 144, Issue 3, p. 263-271
- Publisher Link
- http://dx.doi.org/10.1085/jgp.201311157
- Publisher
- Rockefeller University Press
- Resource Type
- journal article
- Date
- 2014
- Description
- Regulation of the cardiac ryanodine receptor (RyR2) by intracellular Ca²⁺ and Mg²⁺ plays a key role in determining cardiac contraction and rhythmicity, but their role in regulating the human RyR2 remains poorly defined. The Ca²⁺- and Mg²⁺-dependent regulation of human RyR2 was recorded in artificial lipid bilayers in the presence of 2 mM ATP and compared with that in two commonly used animal models for RyR2 function (rat and sheep). Human RyR2 displayed cytoplasmic Ca²⁺ activation (Kₐ = 4 µM) and inhibition by cytoplasmic Mg²⁺ (Ki = 10 µM at 100 nM Ca²⁺) that was similar to RyR2 from rat and sheep obtained under the same experimental conditions. However, in the presence of 0.1 mM Ca²⁺, RyR2s from human were 3.5-fold less sensitive to cytoplasmic Mg²⁺ inhibition than those from sheep and rat. The Kₐ values for luminal Ca²⁺ activation were similar in the three species (35 µM for human, 12 µM for sheep, and 10 µM for rat). From the relationship between open probability and luminal [Ca²⁺], the peak open probability for the human RyR2 was approximately the same as that for sheep, and both were ~10-fold greater than that for rat RyR2. Human RyR2 also showed the same sensitivity to luminal Mg²⁺ as that from sheep, whereas rat RyR2 was 10-fold more sensitive. In all species, modulation of RyR2 gating by luminal Ca²⁺ and Mg²⁺ only occurred when cytoplasmic [Ca²⁺] was <3 µM. The activation response of RyR2 to luminal and cytoplasmic Ca²⁺ was strongly dependent on the Mg²⁺ concentration. Addition of physiological levels (1 mM) of Mg²⁺ raised the Kₐ for cytoplasmic Ca²⁺ to 30 µM (human and sheep) or 90 µM (rat) and raised the Kₐ for luminal Ca²⁺ to ~1 mM in all species. This is the first report of the regulation by Ca²⁺ and Mg²⁺ of native RyR2 receptor activity from healthy human hearts.
- Subject
- adult; animals; calcium/metabolism; cytoplasm/metabolism; magnesium/metabolism
- Identifier
- http://hdl.handle.net/1959.13/1295226
- Identifier
- uon:18980
- Identifier
- ISSN:1540-7748
- Language
- eng
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