An integrated mechanism of cardiomyocyte nuclear Ca²⁺ signaling

In cardiomyocytes, Ca²⁺ plays a central role in governing both contraction and signaling events that regulate gene expression. Current evidence indicates that discrimination between these two critical functions is achieved by segregating Ca²⁺ within subcellular microdomains: transcription is regulated by Ca²⁺ release within nuclear microdomains, and excitation-contraction coupling is regulated by cytosolic Ca²⁺. Accordingly, a variety of agonists that control cardiomyocyte gene expression, such as endothelin-1, angiotensin-II or insulin-like growth factor-1, share the feature of triggering nuclear Ca²⁺ signals. However, signaling pathways coupling surface receptor activation to nuclear Ca²⁺ release, and the phenotypic responses to such signals, differ between agonists. According to earlier hypotheses, the selective control of nuclear Ca²⁺ signals by activation of plasma membrane receptors relies on the strategic localization of inositol trisphosphate receptors at the nuclear envelope. There, they mediate Ca²⁺ release from perinuclear Ca²⁺ stores upon binding of inositol trisphosphate generated in the cytosol, which diffuses into the nucleus. More recently, identification of such receptors at nuclear membranes or perinuclear sarcolemmal invaginations has uncovered novel mechanisms whereby agonists control nuclear Ca²⁺ release. In this review, we discuss mechanisms for the selective control of nuclear Ca²⁺ signals with special focus on emerging models of agonist receptor activation.