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Genetic ablation of ryanodine receptor 2 phosphorylation at Ser‐2808 aggravates Ca 2+ ‐dependent cardiomyopathy by exacerbating diastolic Ca 2+ release
dc.contributor.authorLiu, Binen_US
dc.contributor.authorHo, Hsiang‐tingen_US
dc.contributor.authorVelez‐cortes, Florenciaen_US
dc.contributor.authorLou, Qingen_US
dc.contributor.authorValdivia, Carmen R.en_US
dc.contributor.authorKnollmann, Bjorn C.en_US
dc.contributor.authorValdivia, Hector H.en_US
dc.contributor.authorGyorke, Sandoren_US
dc.date.accessioned2014-05-23T16:00:03Z
dc.date.availableWITHHELD_13_MONTHSen_US
dc.date.available2014-05-23T16:00:03Z
dc.date.issued2014-05-01en_US
dc.identifier.citationLiu, Bin; Ho, Hsiang‐ting ; Velez‐cortes, Florencia ; Lou, Qing; Valdivia, Carmen R.; Knollmann, Bjorn C.; Valdivia, Hector H.; Gyorke, Sandor (2014). "Genetic ablation of ryanodine receptor 2 phosphorylation at Serâ 2808 aggravates Ca 2+ â dependent cardiomyopathy by exacerbating diastolic Ca 2+ release." The Journal of Physiology 592(9): 1957-1973.en_US
dc.identifier.issn0022-3751en_US
dc.identifier.issn1469-7793en_US
dc.identifier.urihttps://hdl.handle.net/2027.42/106986
dc.description.abstractPhosphorylation of the cardiac ryanodine receptor (RyR2) by protein kinase A (PKA) at Ser‐2808 is suggested to mediate the physiological ‘fight or flight’ response and contribute to heart failure by rendering the sarcoplasmic reticulum (SR) leaky for Ca 2+ . In the present study, we examined the potential role of RyR2 phosphorylation at Ser‐2808 in the progression of Ca 2+ ‐dependent cardiomyopathy (CCM) by using mice genetically modified to feature elevated SR Ca 2+ leak while expressing RyR2s that cannot be phosphorylated at this site (S2808A). Surprisingly, rather than alleviating the disease phenotype, constitutive dephosphorylation of Ser‐2808 aggravated CCM as manifested by shortened survival, deteriorated in vivo cardiac function, exacerbated SR Ca 2+ leak and mitochondrial injury. Notably, the deteriorations of cardiac function, myocyte Ca 2+ handling, and mitochondria integrity were consistently worse in mice with heterozygous ablation of Ser‐2808 than in mice with complete ablation. Wild‐type (WT) and CCM myocytes expressing unmutated RyR2s exhibited a high level of baseline phosphorylation at Ser‐2808. Exposure of these CCM cells to protein phosphatase 1 caused a transitory increase in Ca 2+ leak attributable to partial dephosphorylation of RyR2 tetramers at Ser‐2808 from more fully phosphorylated state. Thus, exacerbated Ca 2+ leak through partially dephosphorylated RyR2s accounts for the prevalence of the disease phenotype in the heterozygous S2808A CCM mice. These results do not support the importance of RyR2 hyperphosphorylation in Ca 2+ ‐dependent heart disease, and rather suggest roles for the opposite process, the RyR2 dephosphorylation at this residue in physiological and pathophysiological Ca 2+ signalling.en_US
dc.publisherWiley Periodicals, Inc.en_US
dc.titleGenetic ablation of ryanodine receptor 2 phosphorylation at Ser‐2808 aggravates Ca 2+ ‐dependent cardiomyopathy by exacerbating diastolic Ca 2+ releaseen_US
dc.typeArticleen_US
dc.rights.robotsIndexNoFollowen_US
dc.subject.hlbsecondlevelPhysiologyen_US
dc.subject.hlbtoplevelHealth Sciencesen_US
dc.description.peerreviewedPeer Revieweden_US
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/106986/1/tjp6067.pdf
dc.identifier.doi10.1113/jphysiol.2013.264689en_US
dc.identifier.sourceThe Journal of Physiologyen_US
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dc.owningcollnameInterdisciplinary and Peer-Reviewed


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