Final Report Summary - NUCLEAR CALCIUM (The biology of nuclear calcium: general principles of adaptations and strategies to develop a light-induced signaling enhancer)
The ERC Advanced Grant was instrumental in establishing nuclear calcium as a key signaling end-point in the dialogue between the synapse and the nucleus whose function is to switch-on gene programs that are critical for the long-term implementation of adaptive responses. This work provided solid experimental support for the so-called ‘Nuclear Calcium Hypothesis’ postulated by Hilmar Bading in 2000. This hypothesis predicted that persistent adaptations in the nervous system – both at the cellular and the behavioral level - take place when calcium signals initiated by synaptic activity enter the cell nucleus to activate transcription. The results generated in experiments made possible through the funding by the ERC strongly support this concept. They revealed that nuclear calcium and the gene responses evoked by it are indeed required for various forms of adaptive responses in the nervous system, which included long-term memory formation, acquired neuroprotection and the development of chronic pain. We were able to identify the entire gene pool of about 200 nuclear calcium-regulated genes in the mouse hippocampus, for many of which we were able to demonstrate their role in the control of adaption-associated structural or functional alterations of neurons or neuronal networks. Our work supported by the ERC grant also revealed that, as we predicted, the impact of nuclear calcium as a regulator of adaptations goes far beyond the nervous system. We were able to demonstrate that nuclear calcium is required for the mounting of a productive immune response in human T cells. Moreover, we show that in the absence of nuclear calcium signaling, the fate of stimulated primary (i.e. freshly isolated) human T cells is being re-directed towards anergy and tolerance, indicating that nuclear calcium serves as ‘decision maker’ in the T cell immune response. Finally, we also discovered that nuclear calcium plays an important role in the heart muscle where it controls the process that leads to cardiac hypertrophy. This is a ‚spin-off project’ that was not part of the original ERC grant application but that is tightly linked conceptually and mechanistically to the overall theme of the ERC project. In summary, the ERC funding has allowed us to perform groundbreaking work that established nuclear calcium as an evolutionary conserved (from flies to mammals) master-switch for adaptive responses to environmental signals. The result obtained provided experimental support for a long-standing hypothesis and uncovered a basic cell-biological principle used to control many functions in the brain and in other tissues.