The manner in which Ca 2+-sensitive signaling proteins are activated in contracting cardiomyocytes is an intriguing theoretical problem given that the cytoplasm is continually bathed with systolic Ca 2+ concentrations that should maximally activate most Ca 2+ sensitive signaling kinases and phosphatases. Store-operated Ca 2+ entry, partially attributed to transient receptor potential (TRP) proteins, can mediate activation of the Ca 2+-sensitive phosphatase calcineurin in non-excitable cells. Here we investigated the gain-of-function phenotype associated with TRPC3 expression in the mouse heart using transgenesis to examine the potential role of store-operated Ca 2+ entry in regulating cardiac calcineurin activation and ensuing hypertrophy/myopathy. Adult myocytes isolated from TRPC3 transgenic mice showed abundant store-operated Ca 2+ entry that was inhibited with