Journal
CIRCULATION RESEARCH
Volume 112, Issue 2, Pages 236-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.112.273839
Keywords
cardiomyocytes; excitation-contraction coupling; formamide; interorganelle communication; methyl-beta-cyclodextrin; parvalbumin; pre-T-tubules
Funding
- Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT), Chile [Anillo ACT 1111]
- Programa Fondo de Investigacion Avanzado en Areas Prioritarias (FONDAP) [1501006]
- Swedish Research Council [2009-3364, 2010-4392]
- Wallenberg (Center of Live Imaging of Cells Karolinska Institutet [CLICK]
- Becas Chile
- Parkinson's UK [G-0905] Funding Source: researchfish
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Rationale: The ability of a cell to independently regulate nuclear and cytosolic Ca2+ 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 Ca2+ signals, which allows sarcomere contraction in response to plasma membrane depolarization, but whether there is a similar structure tunneling extracellular stimulation to control nuclear Ca2+ signals locally has not been explored. Objective: To study the role of perinuclear sarcolemma in selective nuclear Ca2+ signaling. Methods and Results: We report here that insulin-like growth factor 1 triggers a fast and independent nuclear Ca2+ 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 Ca2+ signaling and transcriptional upregulation through the perinuclear hydrolysis of phosphatidylinositol 4,5-biphosphate inositol 1,4,5-trisphosphate production, nuclear Ca2+ release, and activation of the transcription factor myocyte-enhancing factor 2C. Genetically engineered Ca2+ buffers-parvalbumin-with cytosolic or nuclear localization demonstrated that the nuclear Ca2+ handling system is physically and functionally segregated from the cytosolic Ca2+ signaling machinery. Conclusions: These data reveal the existence of an inositol 1,4,5-trisphosphate-dependent nuclear Ca2+ toolkit located in direct apposition to the cell surface, which allows the local control of rapid and independent activation of nuclear Ca2+ signaling in response to an extracellular ligand. (Circ Res. 2013;112:236-245.)
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