Functionally redundant 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 (IP 3 R) is a calcium channel expressed in cardiac tissue. There are three IP 3 R isoforms encoded by separate genes. In the heart, the IP 3 R-2 isoform is reported to being most predominant with regards to expression levels and functional significance. The functional roles of IP 3 R-1 and IP 3 R-3 in the heart are essentially unexplored despite measureable expression levels. Here we show that all three IP 3 Rs isoforms are expressed in both neonatal and adult rat ventricular cardiomyocytes and in human heart tissue. All three IP 3 R proteins were expressed throughout the cardiomyocyte sarcoplasmic reticulum. Using isoform specific siRNA, we found that expression of all three IP 3 R isoforms are required for hypertrophic signaling downstream of endothelin-1 stimulation. Mechanistically, IP 3 Rs 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. Our findings highlight previously unidentified functions for IP 3 R isoforms in the heart with significant implications for hypertrophic signaling in animal models and human disease. Significance Hypertrophy is an adaptive response to cardiac stress which can lead to arrhythmias and cardiac failure. The peptide hormone endothelin-1(ET-1) is a potent activator of the hypertrophic program in cardiomyocytes. IP 3 R calcium channels are activated downstream of ET-1 during hypertrophy. We now show that all three IP 3 R proteins are essential for hypertrophic signaling downstream of ET-1. Activation of IP 3 Rs did not lead to nuclear-specific calcium transients but instead led to altered contractility ultimately, leading to NFAT activation and activation of the hypertrophic program. These effects were independent of alterations in IP 3 R protein expression levels both in vitro and in the human failing heart. Our results identify a new paradigm in IP 3 R signaling in the heart with relevance to human disease.