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dc.contributor.authorGalfre, Elena
dc.contributor.authorPitt, Samantha Jane
dc.contributor.authorVenturi, Elisa
dc.contributor.authorSitsapesan, Mano
dc.contributor.authorZaccai, Nathan R
dc.contributor.authorTsaneva-Atanasova, Krasimira
dc.contributor.authorO'Neill, Stephen
dc.contributor.authorSitsapesan, Rebecca
dc.date.accessioned2013-11-05T11:01:14Z
dc.date.available2013-11-05T11:01:14Z
dc.date.issued2012-02-21
dc.identifier.citationGalfre , E , Pitt , S J , Venturi , E , Sitsapesan , M , Zaccai , N R , Tsaneva-Atanasova , K , O'Neill , S & Sitsapesan , R 2012 , ' FKBP12 activates the cardiac ryanodine receptor Ca 2+ -release channel and is antagonised by FKBP12.6 ' , PLoS ONE , vol. 7 , no. 2 , e31956 . https://doi.org/10.1371/journal.pone.0031956en
dc.identifier.issn1932-6203
dc.identifier.otherPURE: 48756016
dc.identifier.otherPURE UUID: e3de541e-7763-4fc7-9726-f6f5df147e78
dc.identifier.otherWOS: 000302873700127
dc.identifier.otherScopus: 84857510566
dc.identifier.otherORCID: /0000-0003-2257-1595/work/60196221
dc.identifier.urihttp://hdl.handle.net/10023/4158
dc.description.abstractChanges in FKBP12.6 binding to cardiac ryanodine receptors (RyR2) are implicated in mediating disturbances in Ca2+-homeostasis in heart failure but there is controversy over the functional effects of FKBP12.6 on RyR2 channel gating. We have therefore investigated the effects of FKBP12.6 and another structurally similar molecule, FKBP12, which is far more abundant in heart, on the gating of single sheep RyR2 channels incorporated into planar phospholipid bilayers and on spontaneous waves of Ca2+-induced Ca2+-release in rat isolated permeabilised cardiac cells. We demonstrate that FKBP12 is a high affinity activator of RyR2, sensitising the channel to cytosolic Ca2+, whereas FKBP12.6 has very low efficacy, but can antagonise the effects of FKBP12. Mathematical modelling of the data shows the importance of the relative concentrations of FKBP12 and FKBP12.6 in determining RyR2 activity. Consistent with the single-channel results, physiological concentrations of FKBP12 (3 µM) increased Ca2+-wave frequency and decreased the SR Ca2+-content in cardiac cells. FKBP12.6, itself, had no effect on wave frequency but antagonised the effects of FKBP12.We provide a biophysical analysis of the mechanisms by which FK-binding proteins can regulate RyR2 single-channel gating. Our data indicate that FKBP12, in addition to FKBP12.6, may be important in regulating RyR2 function in the heart. In heart failure, it is possible that an alteration in the dual regulation of RyR2 by FKBP12 and FKBP12.6 may occur. This could contribute towards a higher RyR2 open probability, 'leaky' RyR2 channels and Ca2+-dependent arrhythmias.
dc.language.isoeng
dc.relation.ispartofPLoS ONEen
dc.rights© 2012 Galfré, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectCalcium-release channelen
dc.subjectFKBPen
dc.subjectHeart diseaseen
dc.subjectArrhythmiaen
dc.subjectR Medicineen
dc.subject.lccRen
dc.titleFKBP12 activates the cardiac ryanodine receptor Ca2+-release channel and is antagonised by FKBP12.6en
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0031956
dc.description.statusPeer revieweden


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