Ca²⁺ elevations are fundamental to cardiac physiology-stimulating contraction and regulating the gene transcription that underlies hypertrophy. How Ca²⁺ specifically controls gene transcription on the background of the rhythmic Ca²⁺ increases required for contraction is not fully understood. Here we identify a hypertrophy-signaling module in cardiac myocytes that explains how Ca²⁺ discretely regulates myocyte hypertrophy and contraction. We show that endothelin-1 (ET-1) stimulates InsP₃-induced Ca²⁺ release (IICR) from perinuclear InsP₃Rs, causing an elevation in nuclear Ca²⁺. Significantly, we show that IICR, but not global Ca²⁺ elevations associated with myocyte contraction, couple to the calcineurin (CnA)/NFAT pathway to induce hypertrophy. Moreover, we found that activation of the CnA/NFAT pathway and hypertrophy by isoproterenol and BayK8644, which enhance global Ca²⁺ fluxes, was also dependent on IICR and nuclear Ca²⁺ elevations. The activation of IICR by these activity-enhancing mediators was explained by their ability to stimulate secretion of autocrine/paracrine ET-1.