Control of Cardiac Hypertrophic Signaling by Inositol 1,4,5-Trisphosphate Receptors

Calcium plays an integral role to many cellular processes including contraction, energy metabolism, gene expression, and cell death. The inositol 1,4,5-trisphosphate receptor (IP3R) is a calcium channel expressed in cardiac tissue. There are three IP3R isoforms encoded by separate genes. In the heart, the IP3R-2 isoform is reported to being most predominant with regards to expression levels and functional significance. The functional roles of IP3R-1 and IP3R-3 in the heart are essentially unexplored despite measureable expression levels. Here we show that genetically encoded calcium indicators are an excellent tool to study calcium dynamics in vitro. As well we explore whether immortalized cell models can be used as an alternative to primary cells to study cardiac hypertrophy. Additionally, we show that all three IP3R proteins were expressed throughout the cardiomyocyte sarcoplasmic reticulum in neonatal and adult rat ventricular cardiomyocytes and in the human heart tissue. Mechanistically, IP3Rs specifically contribute to activation of the hypertrophic program by mediating the positive inotropic effects of endothelin-1 leading to downstream activation of nuclear factor of activated T-cells (NFAT). Our findings highlight previously unidentified functions for IP3R isoforms in the heart with significant implications for hypertrophic signaling in animal models and human disease.