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 (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 all three IP₃Rs isoforms are expressed in both neonatal and adult rat ventricular cardiomyocytes, and in human heart tissue. The three IP₃R proteins are expressed throughout the cardiomyocyte sarcoplasmic reticulum. Using isoform specific siRNA, we found that expression of all three IP₃R isoforms are required for hypertrophic signaling downstream of endothelin-1 stimulation. Mechanistically, IP₃Rs specifically contribute to activation of the hypertrophic program by mediating the positive inotropic effects of endothelin-1 and leading to downstream activation of nuclear factor of activated T-cells. Our findings highlight previously unidentified functions for IP₃R isoforms in the heart with specific implications for hypertrophic signaling in animal models and in human disease.