Ca²⁺ plays a pivotal role in both excitation-contraction coupling (ECC) and activation of Ca²⁺-dependent signaling pathways. One of the remaining questions in cardiac biology is how Ca²⁺-dependent signaling pathways are regulated under conditions of continual Ca²⁺ transients that mediate cardiac contraction during each heartbeat. Ca²⁺-calmodulin–dependent protein kinase II (CaMKII) activation and its ability to regulate histone deacetylase 5 (HDAC5) nuclear shuttling represent a critical Ca²⁺-dependent signaling circuit for controlling cardiac hypertrophy and heart failure, yet the mechanism of activation by Ca²⁺ is not known. In this issue of the JCI, Wu et al. convincingly demonstrate that the inositol 1,4,5-trisphosphate receptor (InsP₃R) is involved in local control of Ca²⁺ for activating CaMKII in the nuclear envelope of adult ventricular cardiac myocytes (see the related article beginning on page 675). The overall paradigm that is demonstrated is the best example of a molecular mechanism whereby signaling is directly regulated by a local Ca²⁺ pool that is disparate or geometrically insensitive to cytosolic Ca²⁺ underlying each contractile cycle.