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Calcium sensing receptor regulates cardiomyocyte function through nuclear calcium
Authors:Zhong Xin  Liu Jun  Lu Fanghao  Wang Yuwen  Zhao Yajun  Dong Shiyun  Leng Xiaoning  Jia Jing  Ren Huan  Xu Changqing  Zhang Weihua
Institution:*Department of Pathophysiology, Harbin Medical University, Harbin 150086, People's Republic of China.
Abstract:Nuclear Ca2+ plays a pivotal role in the regulation of gene expression. IP3 (inositol-1,4,5-trisphosphate) is an important regulator of nuclear Ca2+. We hypothesized that the CaR (calcium sensing receptor) stimulates nuclear Ca2+ release through IICR (IP3-induced calcium release) from perinuclear stores. Spontaneous Ca2+ oscillations and the spark frequency of nuclear Ca2+ were measured simultaneously in NRVMs (neonatal rat ventricular myocytes) using confocal imaging. CaR-induced nuclear Ca2+ 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 Ca2+ signalling through the IP3R pathway. Interestingly, nuclear Ca2+ was released from perinuclear stores by CaR activator-induced cardiomyocyte hypertrophy through the Ca2+-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 Ca2+ transient in NRVMs by increasing fractional Ca2+ release from perinuclear stores, which is involved in cardiac hypertrophy through the CaN/NFAT pathway.
Keywords:calcium sensing receptor (CaR)  hypertrophy  inositol 1  4  5‐trisphosphate receptor (IP3R)  nuclear Ca2+ release
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