Nuclear Ca(2+) plays a pivotal role in the regulation of gene expression. IP3 (inositol-1,4,5-trisphosphate) is an important regulator of nuclear Ca(2+). We hypothesized that the CaR (calcium sensing receptor) stimulates nuclear Ca(2+) release through IICR (IP3-induced calcium release) from perinuclear stores. Spontaneous Ca(2+) oscillations and the spark frequency of nuclear Ca(2+) were measured simultaneously in NRVMs (neonatal rat ventricular myocytes) using confocal imaging. CaR-induced nuclear Ca(2+) release through IICR was abolished by inhibition of CaR and IP3Rs (IP3 receptors). However, no effect on the inhibition of RyRs (ryanodine receptors) was detected. The results suggest that CaR specifically modulates nuclear Ca(2+) signalling through the IP(3)R pathway. Interestingly, nuclear Ca(2+) was released from perinuclear stores by CaR activator-induced cardiomyocyte hypertrophy through the Ca(2+)-dependent phosphatase CaN (calcineurin)/NFAT (nuclear factor of activated T-cells) pathway. We have also demonstrated that the activation of the CaR increased the NRVM protein content, enlarged cell size and stimulated CaN expression and NFAT nuclear translocation in NRVMs. Thus, CaR enhances the nuclear Ca(2+) transient in NRVMs by increasing fractional Ca(2+) release from perinuclear stores, which is involved in cardiac hypertrophy through the CaN/NFAT pathway.