Orphaned ryanodine receptors in the failing heart

Abstract

Heart muscle is characterized by a regular array of proteins and structures that form a repeating functional unit identified as the sarcomere. This regular structure enables tight coupling between electrical activity and Ca 2؉ signaling. In heart failure, multiple cellular defects develop, including reduced contractility, altered Ca 2؉ signaling, and arrhythmias; however, the underlying causes of these defects are not well understood. Here, in ventricular myocytes from spontaneously hypertensive rats that develop heart failure, we identify fundamental changes in Ca 2؉ signaling that are related to restructuring of the spatial organization of the cells. Myocytes display both a reduced ability to trigger sarcoplasmic reticulum Ca 2؉ release and increased spatial dispersion of the transverse tubules (TTs). Remodeled TTs in cells from failing hearts no longer exist in the regularly organized structures found in normal heart cells, instead moving within the sarcomere away from the Z-line structures and leaving behind the sarcoplasmic reticulum Ca 2؉ release channels, the ryanodine receptors (RyRs). These orphaned RyRs appear to be responsible for the dyssynchronous Ca 2؉ sparks that have been linked to blunted contractility and, probably, Ca 2؉ -dependent arrhythmias in diverse models of heart failure. We conclude that the increased spatial dispersion of the TTs and orphaned RyRs lead to the loss of local control and Ca 2؉ instability in heart failure.calcium signaling ͉ local control ͉ dyssynchrony ͉ heart failure ͉ transverse tubules C a 2ϩ sparks, the elementary Ca 2ϩ release events during the excitation-contraction (EC) coupling process in heart (1-5), are triggered by the opening of L-type Ca 2ϩ channels (LCCs) and sum to produce the [Ca 2ϩ ] i transient (6). Each Ca 2ϩ spark arises from a nanometer-sized structural and functional unit or ''couplon,'' which includes both (i) LCCs in the sarcolemma or transverse tubules (TTs), and (ii) a cluster of ryanodine receptors (RyRs) that reside in the sarcoplasmic reticulum (SR) membrane and face the LCCs across a 15-nm gap (7-9). During the cardiac action potential (AP), the nearly simultaneous opening of LCCs synchronizes the triggering of Ca 2ϩ sparks from the RyR clusters (also referred to as Ca 2ϩ release units, or CRUs). Ca 2ϩ signaling in heart failure is characterized by contractile dysfunction (10, 11) (24). In tachycardia-induced HF, Kamp and colleagues (25, 26) have described a regional loss of TTs within ventricular myocytes, but other evidence suggests that TTs remain normal. † † Additionally, many other factors may contribute to arrhythmogenesis, including reduced K ϩ channel expression, increased Na ϩ ͞Ca 2ϩ exchanger activity (21, 27), and altered Ca 2ϩ channel gating (28); therefore, possible links between structural changes and dysfunctional Ca 2ϩ signaling in this HF model remain unclear. In a cell culture investigation using pig ventricular myocytes, dyssynchronous Ca 2ϩ release was observed as the cells in culture dedifferentiated and lost TTs (18)...

Ablation of sarcolipin enhances sarcoplasmic reticulum calcium transport and atrial contractility

“…Therefore, the lack of differences observed between the groups after ISO may result from the inherent limitations. On the other hand, fluo-4 has been widely used for intracellular Ca 2ϩ measurement in cardiac myocytes (25). We also found that loss of SLN function resulted in an increase in rate of contraction in isolated atria.…”

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans

“…Gomez et al showed that receptor concentrations, receptor properties, and SR calcium concentrations remained the same between control and hypertrophied myocytes and consecutively demonstrated that the decrease in [Ca] i was most consistent with partial uncoupling of the L-type calcium channel and ryanodine receptor through increased inter-receptor distance [33]. This process of 'orphaned ryanodine receptors' and disruption of EC coupling was described more recently by Song et al as a model for Ca 2+ dyssynchrony in heart failure [36]. Such a change in the micro-architecture of the dyad would lead to ineffective signaling and result in hypertrophy.…”

Size Matters: Ryanodine Receptor Cluster Size Affects Arrhythmogenic Sarcoplasmic Reticulum Calcium Release

“…However, pathological conditions such as heart failure with altered RyR sensitization1 and structure cluster and T‐tubule–SR organization35, 36, 37, 38, 39, 40 could undermine these intrinsically beneficial effects and contribute to cardiac dysfunction and arrhythmogenesis.…”