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

• Published in: PloS one 2015-04, Vol.10 (4)
• Main Authors: Nakao, Shu, Wakabayashi, Shigeo, Nakamura, Tomoe Y
• Format: Article
• Language: English
• Subjects: Heart cells; Neurons; Neurophysiology; Protein binding
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0125050

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