Inositol 1,4,5-trisphosphate (IP₃) is a second messenger that regulates intracellular Ca²⁺ release through IP₃ receptors located in the sarco(endo)plasmic reticulum of cardiac myocytes. Many prohypertrophic G protein–coupled receptor (GPCR) signaling events lead to IP₃ liberation, although its importance in transducing the hypertrophic response has not been established in vivo.

Here, we generated conditional, heart-specific transgenic mice with both gain- and loss-of-function for IP₃ receptor signaling to examine its hypertrophic growth effects following pathological and physiological stimulation.

Overexpression of the mouse type-2 IP₃ receptor (IP₃R2) in the heart generated mild baseline cardiac hypertrophy at 3 months of age. Isolated myocytes from overexpressing lines showed increased Ca²⁺ transients and arrhythmias in response to endothelin-1 stimulation. Although low levels of IP₃R2 overexpression failed to augment/synergize cardiac hypertrophy following 2 weeks of pressure-overload stimulation, such levels did enhance hypertrophy following 2 weeks of isoproterenol infusion, in response to Gαq overexpression, and/or in response to exercise stimulation. To inhibit IP₃ signaling in vivo, we generated transgenic mice expressing an IP₃ chelating protein (IP₃-sponge). IP₃-sponge transgenic mice abrogated cardiac hypertrophy in response to isoproterenol and angiotensin II infusion but not pressure-overload stimulation. Mechanistically, IP₃R2-enhanced cardiac hypertrophy following isoproterenol infusion was significantly reduced in the calcineurin-Aβ–null background.

These results indicate that IP₃-mediated Ca²⁺ release plays a central role in regulating cardiac hypertrophy downstream of GPCR signaling, in part, through a calcineurin-dependent mechanism.