Stimulus-Dependent Regulation of Nuclear Ca(2+) Signaling in Cardiomyocytes: A Role of Neuronal Calcium Sensor-1

In cardiomyocytes, intracellular calcium (Ca(2+)) transients are elicited by electrical and receptor stimulations, leading to muscle contraction and gene expression, respectively. Although such elevations of Ca(2+)levels ([Ca(2+)]) also occur in the nucleus, the precise mechanism of nuclear [Ca(2+)] regulation during different kinds of stimuli, and its relationship with cytoplasmic [Ca(2+)] regulation are not fully understood. To address these issues, we used a new region-specific fluorescent protein-based Ca(2+) indicator, GECO, together with the conventional probe Fluo-4 AM. We confirmed that nuclear Ca(2+) transients were elicited by both electrical and receptor stimulations in neonatal mouse ventricular myocytes. Kinetic analysis revealed that electrical stimulation-elicited nuclear Ca(2+) transients are slower than cytoplasmic Ca(2+) transients, and chelating cytoplasmic Ca(2+) abolished nuclear Ca(2+) transients, suggesting that nuclear Ca(2+) are mainly derived from the cytoplasm during electrical stimulation. On the other hand, receptor stimulation such as with insulin-like growth factor-1 (IGF-1) preferentially increased nuclear [Ca(2+)] compared to cytoplasmic [Ca(2+)]. Experiments using inhibitors revealed that electrical and receptor stimulation-elicited Ca(2+) transients were mainly mediated by ryanodine receptors and inositol 1,4,5-trisphosphate receptors (IP3Rs), respectively, suggesting different mechanisms for the two signals. Furthermore, IGF-1-elicited nuclear Ca(2+) transient amplitude was significantly lower in myocytes lacking neuronal Ca(2+) sensor-1 (NCS-1), a Ca(2+) binding protein implicated in IP(3)R-mediated pathway in the heart. Moreover, IGF-1 strengthened the interaction between NCS-1 and IP(3)R. These results suggest a novel mechanism for receptor stimulation-induced nuclear [Ca(2+)] regulation mediated by IP3R and NCS-1 that may further fine-tune cardiac Ca(2+) signal regulation.