Local Control of Nuclear Ca2+ Signalling in Cardiac Myocytes by Perinuclear Microdomains of Sarcolemmal IGF-1 Receptors
Rationale: The ability of a cell to independently regulate nuclear and cytosolic Ca2+ signalling is currently attributed to the differential distribution of IP3R channel isoforms in the nucleoplasmic versus the endoplasmic reticulum. In cardiac myocytes, T-tubules confer the necessary compartmentation of Ca2+ signals that 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+ signalling.
Methods and Results: We report here that IGF-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 IGF-1R signalling complexes present in perinuclear invaginations of the plasma membrane. The perinuclear IGF-1R pool connects extracellular stimulation to local activation of nuclear Ca2+-signalling and transcriptional up-regulation through the perinuclear hydrolysis of PIP2, IP3 production, nuclear Ca2+ release and activation of the transcription factor MEF2C. 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+ signalling machinery.
Conclusions: These data reveal the existence of an IP3-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+ signalling in response to an extracellular ligand.
- Ca2+ regulation
- Calcium signaling
- Cardiac myocytes
- Excitation-contraction coupling
- Insulin-like growth factor-1
- Signal transduction
- ; pre-T-tubules
- inter-organelle communication
- Received May 22, 2012.
- Accepted October 31, 2012.
- Copyright © 2012, American Heart Association