Posttranslational modifications of cardiac ryanodine receptors: Ca2+ signaling and EC-coupling

Abstract

In cardiac muscle, a number of posttranslational protein modifications can alter the function of the Ca2+ release channel of the sarcoplasmic reticulum (SR), also known as the ryanodine receptor (RyR). During every heartbeat RyRs are activated by the Ca2+-induced Ca2+ release mechanism and contribute a large fraction of the Ca2+ required for contraction. Some of the posttranslational modifications of the RyR are known to affect its gating and Ca2+ sensitivity. Presently, research in a number of laboratories is focussed on RyR phosphorylation, both by PKA and CaMKII, or on RyR modifications caused by reactive oxygen and nitrogen species (ROS / RNS). Both classes of posttranslational modifications are thought to play important roles in the physiological regulation of channel activity, but are also known to provoke abnormal alterations during various diseases. Only recently it was realized that several types of posttranslational modifications are tightly connected and form synergistic (or antagonistic) feed-back loops resulting in additive and potentially detrimental downstream effects. This review summarizes recent findings on such posttranslational modifications, attempts to bridge molecular with cellular findings, and opens a perspective for future work trying to understand the ramifications of crosstalk in these multiple signaling pathways. Clarifying these complex interactions will be important in the development of novel therapeutic approaches, since this may form the foundation for the implementation of multi-pronged treatment regimes in the future.

Mitochondrial dysfunctions during progression of dystrophic cardiomyopathy

“…As disease progresses, intracellular Ca 2+ homeostasis gets more deregulated due to synergetic activation of additional mechanisms that contribute to increased sensitivity of RyRs [12]. Altogether the enhanced Ca 2+ signals eventually lead to cytosolic and mitochondrial Ca 2+ overload.…”

“…Most of the patients develop cardiomyopathy in their teens, and many of them succumb to cardiac complications [7–9]. The disease is caused by a genetic defect – the lack of a functional cytoskeleton protein dystrophin [10,11] and it’s phenotype exhibits numerous cellular pathological features [12,13]. Recently we reported severe oxidative stress (resulting from overexpression of sarcolemmal NAD(P)H oxidase type II (NOX2)) and augmented intracellular Ca 2+ signaling in hearts of mdx mice well before clinical manifestations of the disease [1,14].…”

A change of heart: oxidative stress in governing muscle function?

“…Whether oxidative PKA and PKG activation has any functional consequences in cardiomyocytes remains to be investigated. Prominent examples are the RyRs, which can be modified upon oxidation, S-nitrosation and Sglutathionylation (Wehrens et al 2005;Meissner 2010;Niggli et al 2013).The RyRs are known to be sensitive to redox modifications: tetrameric RyR2 contains 364 cysteines, 84 of which have free thiol groups that can be S-nitrosylated (González et al 2008) glutathionylated (Sánchez et al 2005).…”

Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

“…The phosphorylation of these serines increases the resting open probability of RyR2 promoting a Ca 2+ leak from the sarcoplasmic reticulum. 22,23 To evaluate the activity of the RyR2 channel in conditions that mimic catecholaminergic stress, calcium-imaging experiments were performed using forskolin to increase intracellular levels of cAMP. Caffeine sensitivity of the G357S channel was higher than that of the WT channel in the presence of forskolin ( Figure 4A and B).…”