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dc.contributor.advisorJones, Peter
dc.contributor.advisorMunro, Michelle
dc.contributor.authorHinton, Lucas
dc.date.available2019-11-21T20:11:23Z
dc.date.copyright2019
dc.identifier.citationHinton, L. (2019). Regulation of cardiac ryanodine receptor 2 by protein kinase CK2 (Thesis, Bachelor of Biomedical Sciences with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/9816en
dc.identifier.urihttp://hdl.handle.net/10523/9816
dc.description.abstractThe cardiac muscle ryanodine receptor (RyR2) is an intracellular Ca2+ channel responsible for the release of Ca2+ during excitation-contraction coupling. It is also implicated in pathological store-overload-induced Ca2+ release (SOICR), a common trigger for life-threatening arrhythmias. Phosphorylation plays a vital role in the modulation of RyR2 and SOICR, and recent work has outlined a possible relationship between a novel protein kinase, CK2 (formerly casein kinase II), and two RyR2 residues, S2692/93. The aim of this study was to investigate whether the interaction between these two RyR2 residues and CK2 leads to modification of RyR2 function and how this may impact SOICR susceptibility. A knock-in heterozygous S2692/93A (S2692/93A+/-) mouse model with modified RyR2 residues preventing CK2-associated phosphorylation was generated. Confocal microscopy demonstrated that isolated S2692/93A+/- cardiomyocytes exhibited increased SOICR frequency compared with baseline. This was especially notable at lower extracellular Ca2+ levels; in these conditions, pacing induced a significantly higher SOICR frequency compared with baseline in S2692/93A+/- mice (0.082 ± 0.027 Sparks/100 μm/s-1, n = 8) compared with their wt littermates (0.003 ± 0.003 Sparks/100 μm/s-1, n = 5, p= 0.01). An in vivo analysis was conducted using both echocardiography and electrocardiogram to determine whether the cellular-level dysfunction seen in the S2692/93A+/- mice translated into an increased arrhythmia susceptibility. This analysis revealed no significant difference in key cardiac parameters at baseline or in response to acute pharmacological stress (adrenaline/caffeine) between S2692/93A+/- mice and their wt littermates. Taken together, these findings demonstrate for the first time that RyR2 can be phosphorylated at S2692/93 in vivo. Unlike previously identified RyR2-associated kinases such as calmodulin-dependent protein kinase II and calmodulin- dependent protein kinase II, CK2-associated phosphorylation appears to have a cardioprotective effect, reducing SOICR propensity. Why this cellular dysfunction did not translate into an increased arrhythmic susceptibility, however, remains to be established.
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.subjectNew Zealand
dc.subjectArrthythmia
dc.subjectRyR2
dc.subjectCK2
dc.titleRegulation of cardiac ryanodine receptor 2 by protein kinase CK2
dc.typeThesis
dc.date.updated2019-11-21T09:26:32Z
dc.language.rfc3066en
thesis.degree.disciplinePhysiology
thesis.degree.nameBachelor of Biomedical Sciences with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.interloanno
otago.openaccessAbstract Only
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