Local control of nuclear calcium signaling in cardiac myocytes by perinuclear microdomains of sarcolemmal insulin-like growth factor 1 receptors

Rationale: The ability of a cell to independently regulate nuclear and cytosolic Ca signaling is currently attributed to the differential distribution of inositol 1,4,5-trisphosphate receptor channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca signals, which allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca signaling. Methods and Results: We report here that insulin-like growth factor 1 triggers a fast and independent nuclear Ca signal in neonatal rat cardiac myocytes, human embryonic cardiac myocytes, and adult rat cardiac myocytes. This fast and localized response is achieved by activation of insulin-like growth factor 1 receptor signaling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear insulin-like growth factor 1 receptor pool connects extracellular stimulation to local activation of nuclear Ca signaling and transcriptional upregulation through the perinuclear hydrolysis of phosphatidylinositol 4,5-biphosphate inositol 1,4,5-trisphosphate production, nuclear Ca release, and activation of the transcription factor myocyte-enhancing factor 2C. Genetically engineered Ca buffers-parvalbumin-with cytosolic or nuclear localization demonstrated that the nuclear Ca handling system is physically and functionally segregated from the cytosolic Ca signaling machinery. Conclusions: These data reveal the existence of an inositol 1,4,5-trisphosphate-dependent nuclear Ca toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca signaling in response to an extracellular ligand.