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.

Functional local crosstalk of inositol 1,4,5-trisphosphate receptor- and ryanodine receptor-dependent Ca2+ release in atrial cardiomyocytes.

AIMS: Enhanced inositol 1,4,5-trisphosphate receptor (InsP3R2) expression has been associated with a variety of proarrhythmogenic cardiac disorders. The functional interaction between the two major Ca2+ release mechanisms in cardiomyocytes, Ca2+ release mediated by ryanodine receptors (RyR2s) and InsP3-induced intracellular Ca2+ release (IP3ICR) remains enigmatic. We aimed at identifying characterizing local IP3ICR events, and elucidating functional local crosstalk mechanisms between cardiac InsP3R2s and RyR2s under conditions of enhanced cardiac specific InsP3R2 activity. METHODS AND RESULTS: Using confocal imaging and two-dimensional spark analysis, we demonstrate in atrial myocytes (mouse model cardiac specific overexpressing InsP3R2s) that local Ca2+ release through InsP3Rs (Ca2+ puff) directly activates RyRs and triggers elementary Ca2+ release events (Ca2+ sparks). In the presence of increased intracellular InsP3 concentrations IP3ICR can modulate RyRs openings and Ca2+ spark probability. We show as well that IP3ICR remains under local control of Ca2+ release through RyRs. CONCLUSIONS: Our results support the concept of bidirectional interaction between RyRs and InsP3Rs (i.e. Ca2+ sparks and Ca2+ puffs) in atrial myocytes. We conclude that highly efficient InsP3 dependent SR-Ca2+ flux constitute the main mechanism of functional crosstalk between InsP3Rs and RyRs resulting in more Ca2+ sensitized RyRs to trigger subsequent Ca2+-induced Ca2+ release activation. In this way, bidirectional local interaction of both SR-Ca2+ release channels may contribute to the shaping of global Ca2+ transients and thereby to contractility in cardiac myocytes.