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dc.contributor.advisorJones, Peter
dc.contributor.authorWong, Alexander
dc.date.available2017-12-18T20:01:45Z
dc.date.copyright2017
dc.identifier.citationWong, A. (2017). PKCε Phosphorylation of RyR2: A Novel Link between Diabetes and Arrhythmia. (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/7791en
dc.identifier.urihttp://hdl.handle.net/10523/7791
dc.description.abstractCardiovascular disease (CVD) is the leading cause of death in the world. Arrhythmia is a type of CVD which can be caused by store overload induced calcium (Ca2+) release (SOICR) in cardiomyocytes. SOICR occurs through the cardiac ryanodine receptor (RyR2). RyR2 phosphorylation is known to be a cause of SOICR. Patients with diabetes (DM) have an increased risk of arrhythmia as well as an increase in RyR2 phosphorylation by certain kinases. One kinase activated in DM is Protein Kinase C (PKC). PKC isoforms; α,ε, β2 and δ have an increased activity in the DM heart. Our study aimed to determine the effect of PKC on RyR2 in regard to SOICR. We hypothesised that activation or overexpression of PKC would result in an increase in SOICR consistent with RyR2 phosphorylation by other kinases. SOICR was examined in HEK293 cells expressing RyR2 with or without PKC overexpression in the presence and absence of a PKC activator (Dic8) and inhibitor (Go6983). Dic8, as well as Go6983, resulted in an increase in the occurrence of SOICR. Recent studies in the lab show that ATP analogues directly affect RyR2 resulting in SOICR, making the results of Go6983 hard to interpret. Overexpression of PKCα, with or without Dic8, resulted in small increase in the occurrence of SOICR. However, overexpression of PKCε, with or without Dic8, resulted in a large increase in the occurrence of SOICR. The propensity for SOICR is determined by the sensitivity of RyR2 to sarcoplasmic reticulum (SR) Ca2+. To study if PKC altered the sensitivity of RyR2 to SR Ca2+a SR targeted Ca2+ sensing protein, D1ER, was used. Overexpression of PKCα resulted in no change in the sensitivity of RyR2 to SR Ca2+, however, consistent with the increase in the propensity for SOICR, PKCε resulted in an increase in the sensitivity of RyR2 to SR Ca2+. Our data indicate that akin to other kinases, PKCε can increase SOICR through the RyR2 due to an increase in RyR2’s sensitivity to SR Ca2+. These findings may represent a novel link through which DM mediated changes in cell signalling increase the risk of arrhythmias.
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectRyR2
dc.subjectArrythmia
dc.subjectDiabetes
dc.subjectCalcium
dc.subjectSOICR
dc.subjectPhosphorylation
dc.subjectPKC
dc.titlePKCε Phosphorylation of RyR2: A Novel Link between Diabetes and Arrhythmia.
dc.typeThesis
dc.date.updated2017-12-18T03:52:15Z
dc.language.rfc3066en
thesis.degree.disciplinePhysiology
thesis.degree.nameBachelor of Biomedical Sciences with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.openaccessOpen
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