Accessibility Skip to Global Navigation Skip to Local Navigation Skip to Content Skip to Search Skip to Site Map Menu

Regulation of cardiac ryanodine receptors (RyR2) by protein kinase CK2 and small molecule kinase inhibitors

The cardiac ryanodine receptor (RyR2) is an intracellular Ca2+ release channel located in the sarcoplasmic reticulum (SR) and is a key component in excitation-contraction coupling (the process of contraction) in cardiac muscle. However, in addition to its role in normal contraction, when the SR store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs through RyR2; a process we refer to as store-overload-induced Ca2+ release (SOICR). In turn SOICR can give rise to delayed after depolarisations (DADs) a common trigger of arrhythmia. Phosphorylation plays a vital role in the regulation of the RyR2 channel and occurs in response to physiological and disease stimuli. This study has investigated a role for novel protein kinase CK2 (CK2) phosphorylation of RyR2 and its effect on SOICR.

I used human embryonic kidney 293 (HEK293) cells expressing RyR2 coupled with Ca2+ imaging, mass spectrometry (MS), site-directed mutagenesis (SDM) and biochemical approaches to investigate the impact of CK2 on Ca2+ release via RyR2. The study has identified identified three novel CK2 phosphorylation sites within RyR2. Studying these sites directly showed that, contrary to PKA and CaMKII phosphorylation of RyR2, CK2 phosphorylation is required to prevent SOICR.

In addition, I also studied the regulation of RyR2 by small molecule kinase inhibitors associated with cardiotoxic side effects in patients. I found that class I kinase inhibitors resulted in an increase in SOICR, whereas class II kinase inhibitors had no effect in either HEK cells or rat cardiomyocytes. These data provide a novel pathway through which certain anti-cancer drugs may be cardiotoxic.

Date Monday, 29 October 2018
Time 1:00pm - 2:00pm
Audience All University
Event Category Health Sciences
Event Type Departmental Seminar
LocationHercus d'Ath Lecture Theatre, Great King Street

Save this event