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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

Walweel, K; Li, Jioa; Molenaar, Peter; Imtiaz, Mohammad S; Quail, Anthony; dos Remedios, Cristobal; Beard, Nicole; Dulhunty, Angela; vanHelden, Dirk F; Laver, Derek R

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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)...[Show more]

dc.contributor.authorWalweel, K
dc.contributor.authorLi, Jioa
dc.contributor.authorMolenaar, Peter
dc.contributor.authorImtiaz, Mohammad S
dc.contributor.authorQuail, Anthony
dc.contributor.authordos Remedios, Cristobal
dc.contributor.authorBeard, Nicole
dc.contributor.authorDulhunty, Angela
dc.contributor.authorvanHelden, Dirk F
dc.contributor.authorLaver, Derek R
dc.date.accessioned2015-12-08T22:46:29Z
dc.identifier.issn0022-1295
dc.identifier.urihttp://hdl.handle.net/1885/38169
dc.description.abstractRegulation 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.publisherRockefeller University Press
dc.rightsAuthor/s retain copyright
dc.sourceJournal of General Physiology
dc.titleDifferences 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.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume144
dc.date.issued2014
local.identifier.absfor060100 - BIOCHEMISTRY AND CELL BIOLOGY
local.identifier.absfor110300 - CLINICAL SCIENCES
local.identifier.ariespublicationu4693331xPUB158
local.type.statusPublished Version
local.contributor.affiliationWalweel, K, University of Newcastle
local.contributor.affiliationLi, Jioa, University of Newcastle
local.contributor.affiliationMolenaar, Peter, Queensland University of Technology and Princle Charles Hospital
local.contributor.affiliationImtiaz, Mohammad S, University of Newcastle
local.contributor.affiliationQuail, Anthony, University of Newcastle
local.contributor.affiliationdos Remedios, Cristobal, University of Sydney
local.contributor.affiliationBeard, Nicole, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationDulhunty, Angela, College of Medicine, Biology and Environment, ANU
local.contributor.affiliationvanHelden, Dirk F, University of Newcastle
local.contributor.affiliationLaver, Derek R, University of Newcastle
local.bibliographicCitation.issue3
local.bibliographicCitation.startpage263
local.bibliographicCitation.lastpage271
local.identifier.doi10.1085/jgp.201311157
dc.date.updated2015-12-08T11:01:42Z
local.identifier.scopusID2-s2.0-84907311139
local.identifier.thomsonID000342748500007
dcterms.accessRightsOpen Access
CollectionsANU Research Publications

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