Nuclear Ca2+ sparks and waves mediated by inositol 1,4,5-trisphosphate receptors in neonatal rat cardiomyocytes

Dynamic nuclear Ca2+ signals play pivotal roles in diverse cellular functions including gene transcription, cell growth, differentiation, and apoptosis. Here we report a novel nuclear Ca2+ regulatory mechanism mediated by inositol 1,4,5-trisphosphate receptors (IP3Rs) around the nucleus in developing cardiac myocytes. Activation of IP3Rs by α1-adrenergic receptor (α1AR) stimulation or by IP3 application (in saponin-permeabilized cells) increases Ca2+ spark frequency preferentially in the region around the nucleus in neonatal rat ventricular myocytes. A nuclear enrichment of IP3R distribution supports the higher responsiveness of Ca2+ release in this particular region. Strikingly, we observed “nuclear Ca2+waves” that engulf the entire nucleus without spreading into the bulk cytosol. α1AR stimulation enhances the occurrence of nuclear Ca2+ waves and confers them the ability to trigger cytosolic Ca2+ waves via IP3R-dependent pathways. This finding accounts, at least partly, for a profound frequency-dependent modulation of global Ca2+ oscillations during α1AR stimulation. Thus, IP3R-mediated Ca2+ waves traveling in the nuclear region provide active, autonomous regulation of nuclear Ca2+ signaling, which provides for not only the local signal transduction, but also a pacemaker to drive global Ca2+ transient in the context of α1AR stimulation in developing cardiac myocytes.