Local increases in Ca²⁺ concentration ([Ca²⁺]) in the cytoplasm and nucleus of cardiac myocytes are key to excitation-contraction and excitation-transcription coupling, respectively. Ca²⁺ increases in these compartments are brought about by Ca²⁺ release from internal stores, i.e. the sarcoplasmic reticulum (SR) and the nuclear envelope (NE). Dysregulation of Ca²⁺ release from these stores may elicit arrhythmias and cellular remodeling.

In atrial myocytes – due to a lack of T-tubules – SR Ca²⁺ release during excitation-contraction coupling is spatially and temporally inhomogenous. Depolarization first triggers Ca²⁺ release from the subsarcolemmal SR, from where it spreads centripetally via active Ca²⁺-induced Ca²⁺ release from the central SR to induce contraction. SR Ca²⁺ release during excitation-contraction coupling occurs mainly via functional units of ryanodine receptors (RyRs), which are distributed in a sarcomeric, grid-like pattern distanced ~2mm apart. SR Ca²⁺ release is regulated by the microenvironment of RyRs. Local disturbances of RyR-mediated Ca²⁺ release (e.g. by inhibition of glycolysis) may result in spatially confined, subcellular Ca²⁺ alternans and generation of arrhythmogenic [Ca²⁺] waves. In addition to RyRs, atrial myocytes also contain IP₃ receptors (IP₃Rs), albeit at much lower density. Activation of subsarcolemmal IP₃Rs, however, through IP₃ generated from ET receptors coupling to phospholipase C, induces spontaneous diastolic Ca²⁺ release and arrhythmic extra-contractions.

The nucleus is separated from the cytoplasm by the NE. Due to the presence of nuclear pores, however, cytoplasmic Ca²⁺ may also diffuse into the nucleoplasm. Thus, during excitation-contraction coupling [Ca²⁺] also increases passively in the nucleus, but with a considerable delay as compared to the cytoplasmic [Ca²⁺] transient. The NE is a functional Ca²⁺ store directly connected to the SR. It forms tubular structures traversing the nucleoplasm, i.e. the nucleoplasmic reticulum, and contains RyRs and IP₃Rs as Ca²⁺ release channels. Thus, the NE has the potential to regulate actively local Ca²⁺ in the nucleoplasm and, thereby, to modulate transcription (excitation-transcription coupling). Activation of nuclear IP₃Rs causes a selective increase in the nuclear [Ca²⁺] transient, thus demonstrating directly that nuclear Ca²⁺ may be regulated independently from cytoplasmic Ca²⁺.

In conclusion, spatial Ca²⁺ signaling in cardiac myocytes depends on the subcellular distribution, local regulation and activation of RyRs and IP₃Rs. It is essential for physiological processes such as excitation-contraction and excitation-transcription coupling but may also be involved in pathological processes such as arrhythmogenesis and the development of hypertrophy.