Regulation of cardiac ryanodine receptor 2 by protein kinase CK2
Hinton, Lucas
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Hinton, 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/10523/9816
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http://hdl.handle.net/10523/9816
Abstract:
The 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.
Date:
2019
Advisor:
Jones, Peter; Munro, Michelle
Degree Name:
Bachelor of Biomedical Sciences with Honours
Degree Discipline:
Physiology
Publisher:
University of Otago
Keywords:
New Zealand; Arrthythmia; RyR2; CK2
Research Type:
Thesis
Languages:
English
Collections
- Physiology [174]
- Thesis - Honours [383]