Dual mode of action of IP₃-dependent SR-Ca²⁺ release on local and global SR-Ca²⁺ release in ventricular cardiomyocytes

In heart muscle, the physiological function of IP₃-induced Ca²⁺ release (IP₃ICR) from the sarcoplasmic reticulum (SR) is still the subject of intense study. A role of IP₃ICR may reside in modulating Ca²⁺-dependent cardiac arrhythmogenicity. Here we observe the propensity of spontaneous intracellular Ca²⁺ waves (SCaW) driven by Ca²⁺-induced Ca²⁺ release (CICR) in ventricular myocytes as a correlate of arrhythmogenicity on the organ level. We observe a dual mode of action of IP₃ICR on SCaW generation in an IP₃R overexpression model. This model shows a mild cardiac phenotype and mimics pathophysiological conditions of increased IP₃R activity. In this model, IP₃ICR was able to increase or decrease the occurrence of SCaW depending on global Ca²⁺ activity. This IP₃ICR-based regulatory mechanism can operate in two "modes" depending on the intracellular CICR activity and efficiency (e.g. SCaW and/or local Ryanodine Receptor (RyR) Ca²⁺ release events, respectively): a) in a mode that augments the CICR mechanism at the cellular level, resulting in improved excitation-contraction coupling (ECC) and ultimately better contraction of the myocardium, and b) in a protective mode in which the CICR activity is curtailed to prevent the occurrence of Ca²⁺ waves at the cellular level and thus reduce the probability of arrhythmogenicity at the organ level.