Calcium (Ca) is a universal intracellular second messenger. In muscle, Ca is best known for its role in contractile activation. However, in recent years the critical role of Ca in other myocyte processes has become increasingly clear. This review focuses on Ca signaling in cardiac myocytes as pertaining to electrophysiology (including action potentials and arrhythmias), excitation-contraction coupling, modulation of contractile function, energy supply-demand balance (including mitochondrial function), cell death, and transcription regulation. Importantly, although such diverse Ca-dependent regulations occur simultaneously in a cell, the cell can distinguish distinct signals by local Ca or protein complexes and differential Ca signal integration.

Abnormal release of Ca from sarcoplasmic reticulum (SR) via the cardiac ryanodine receptor (RyR2) may contribute to contractile dysfunction and arrhythmogenesis in heart failure (HF). We previously demonstrated decreased Ca transient amplitude and SR Ca load associated with increased Na/Ca exchanger expression and enhanced diastolic SR Ca leak in an arrhythmogenic rabbit model of nonischemic HF. Here we assessed expression and phosphorylation status of key Ca handling proteins and measured SR Ca leak in control and HF rabbit myocytes. With HF, expression of RyR2 and FK-506 binding protein 12.6 (FKBP12.6) were reduced, whereas inositol trisphosphate receptor (type 2) and Ca/calmodulin–dependent protein kinase II (CaMKII) expression were increased 50% to 100%. The RyR2 complex included more CaMKII (which was more activated) but less calmodulin, FKBP12.6, and phosphatases 1 and 2A. The RyR2 was more highly phosphorylated by both protein kinase A (PKA) and CaMKII. Total phospholamban phosphorylation was unaltered, although it was reduced at the PKA site and increased at the CaMKII site. SR Ca leak in intact HF myocytes (which is higher than in control) was reduced by inhibition of CaMKII but was unaltered by PKA inhibition. CaMKII inhibition also increased SR Ca content in HF myocytes. Our results suggest that CaMKII-dependent phosphorylation of RyR2 is involved in enhanced SR diastolic Ca leak and reduced SR Ca load in HF, and may thus contribute to arrhythmias and contractile dysfunction in HF.

—Ventricular arrhythmias and contractile dysfunction are the main causes of death in human heart failure (HF). In a rabbit HF model reproducing these same aspects of human HF, we demonstrate that a 2-fold functional upregulation of Na ⁺ -Ca ²⁺ exchange (NaCaX) unloads sarcoplasmic reticulum (SR) Ca ²⁺ stores, reducing Ca ²⁺ transients and contractile function. Whereas β-adrenergic receptors (β-ARs) are progressively downregulated in HF, residual β-AR responsiveness at this critical HF stage allows SR Ca ²⁺ load to increase, causing spontaneous SR Ca ²⁺ release and transient inward current carried by NaCaX. A given Ca ²⁺ release produces greater arrhythmogenic inward current in HF (as a result of NaCaX upregulation), and ≈50% less Ca ²⁺ release is required to trigger an action potential in HF. The inward rectifier potassium current ( I _K1 ) is reduced by 49% in HF, and this allows greater depolarization for a given NaCaX current. Partially blocking I _K1 in control cells with barium mimics the greater depolarization for a given current injection seen in HF. Thus, we present data to support a novel paradigm in which changes in NaCaX and I _K1 , and residual β-AR responsiveness, conspire to greatly increase the propensity for triggered arrhythmias in HF. In addition, NaCaX upregulation appears to be a critical link between contractile dysfunction and arrhythmogenesis.

CaMKII is known to be pathologically activated in heart failure and arrhythmias; here it is shown that glucose-induced CaMKII activation via O-linked glycosylation might contribute to cardiac pathology in diabetes. During heart failure the enzyme Ca2+/calmodulin-dependent protein kinase II (CaMKII) becomes autonomously activated, potentially disrupting ion-channel gating and calcium handling. This paper suggests that glucose-induced CaMKII activation might contribute to cardiac pathology in diabetes. The authors show that high glucose induces covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc) at a specific residue. This activates CaMKII and enhances spontaneous calcium release events that can contribute to arrhythmias. Increased levels of O-GlcNAc-modified CaMKII were found in the hearts and brains of diabetic patients and in rats. In addition, signs of arrhythmia in isolated perfused rat hearts were prevented by CaMKII inactivation or by blocking O-GlcNAc modification. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with important regulatory functions in the heart and brain, and its chronic activation can be pathological. CaMKII activation is seen in heart failure, and can directly induce pathological changes in ion channels, Ca2+ handling and gene transcription1. Here, in human, rat and mouse, we identify a novel mechanism linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a key risk factor for heart2 and neurodegenerative diseases3,4. Acute hyperglycaemia causes covalent modification of CaMKII by O-linked N-acetylglucosamine (O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII autonomously, creating molecular memory even after Ca2+ concentration declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of diabetic humans and rats. In cardiomyocytes, increased glucose concentration significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic reticulum Ca2+ release events that can contribute to cardiac mechanical dysfunction and arrhythmias1. These effects were prevented by pharmacological inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact perfused hearts, arrhythmias were aggravated by increased glucose concentration through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of CaMKII is a novel signalling event in pathways that may contribute critically to cardiac and neuronal pathophysiology in diabetes and other diseases.