Abstract
Dynamic nuclear Ca(2+) signals play pivotal roles in diverse cellular functions including gene transcription, cell growth, differentiation, and apoptosis. Here we report a novel nuclear Ca(2+) regulatory mechanism mediated by inositol 1,4,5-trisphosphate receptors (IP(3)Rs) around the nucleus in developing cardiac myocytes. Activation of IP(3)Rs by alpha(1)-adrenergic receptor (alpha(1)AR) stimulation or by IP(3) application (in saponin-permeabilized cells) increases Ca(2+) spark frequency preferentially in the region around the nucleus in neonatal rat ventricular myocytes. A nuclear enrichment of IP(3)R distribution supports the higher responsiveness of Ca(2+) release in this particular region. Strikingly, we observed "nuclear Ca(2+)waves" that engulf the entire nucleus without spreading into the bulk cytosol. alpha(1)AR stimulation enhances the occurrence of nuclear Ca(2+) waves and confers them the ability to trigger cytosolic Ca(2+) waves via IP(3)R-dependent pathways. This finding accounts, at least partly, for a profound frequency-dependent modulation of global Ca(2+) oscillations during alpha(1)AR stimulation. Thus, IP(3)R-mediated Ca(2+) waves traveling in the nuclear region provide active, autonomous regulation of nuclear Ca(2+) signaling, which provides for not only the local signal transduction, but also a pacemaker to drive global Ca(2+) transient in the context of alpha(1)AR stimulation in developing cardiac myocytes.