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
dc.contributor.author | Walweel, K | |
dc.contributor.author | Li, Jioa | |
dc.contributor.author | Molenaar, Peter | |
dc.contributor.author | Imtiaz, Mohammad S | |
dc.contributor.author | Quail, Anthony | |
dc.contributor.author | dos Remedios, Cristobal | |
dc.contributor.author | Beard, Nicole | |
dc.contributor.author | Dulhunty, Angela | |
dc.contributor.author | vanHelden, Dirk F | |
dc.contributor.author | Laver, Derek R | |
dc.date.accessioned | 2015-12-08T22:46:29Z | |
dc.date.issued | 2014 | |
dc.date.updated | 2015-12-08T11:01:42Z | |
dc.description.abstract | 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. | |
dc.identifier.issn | 0022-1295 | |
dc.identifier.uri | http://hdl.handle.net/1885/38169 | |
dc.publisher | Rockefeller University Press | |
dc.rights | Author/s retain copyright | en_AU |
dc.source | Journal of General Physiology | |
dc.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 | |
dc.type | Journal article | |
dcterms.accessRights | Open Access | en_AU |
local.bibliographicCitation.issue | 3 | |
local.bibliographicCitation.lastpage | 271 | |
local.bibliographicCitation.startpage | 263 | |
local.contributor.affiliation | Walweel, K, University of Newcastle | |
local.contributor.affiliation | Li, Jioa, University of Newcastle | |
local.contributor.affiliation | Molenaar, Peter, Queensland University of Technology and Princle Charles Hospital | |
local.contributor.affiliation | Imtiaz, Mohammad S, University of Newcastle | |
local.contributor.affiliation | Quail, Anthony, University of Newcastle | |
local.contributor.affiliation | dos Remedios, Cristobal, University of Sydney | |
local.contributor.affiliation | Beard, Nicole, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | Dulhunty, Angela, College of Medicine, Biology and Environment, ANU | |
local.contributor.affiliation | vanHelden, Dirk F, University of Newcastle | |
local.contributor.affiliation | Laver, Derek R, University of Newcastle | |
local.contributor.authoremail | u8404877@anu.edu.au | |
local.contributor.authoruid | Beard, Nicole, u9802885 | |
local.contributor.authoruid | Dulhunty, Angela, u8404877 | |
local.description.notes | Imported from ARIES | |
local.identifier.absfor | 060100 - BIOCHEMISTRY AND CELL BIOLOGY | |
local.identifier.absfor | 110300 - CLINICAL SCIENCES | |
local.identifier.ariespublication | u4693331xPUB158 | |
local.identifier.citationvolume | 144 | |
local.identifier.doi | 10.1085/jgp.201311157 | |
local.identifier.scopusID | 2-s2.0-84907311139 | |
local.identifier.thomsonID | 000342748500007 | |
local.identifier.uidSubmittedBy | u4693331 | |
local.type.status | Published Version |
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