Abstract
Many forms of signal transduction occur when Ca2+ enters the cytoplasm of a cell. It has been generally thought that there is a fast buffer that rapidly reduces the free Ca2+ level and that it is this buffered level of Ca2+ that triggers downstream biochemical processes, notably the activation of calmodulin (CaM) and the resulting activation of CaM-dependent enzymes. Given the importance of these transduction processes, it is crucial to understand exactly how Ca2+ activates CaM. We have determined the rate at which Ca2+ binds to CaM and found that Ca2+ binds more rapidly to CaM than to other Ca2+-binding proteins. This property of CaM and its high concentration support a new view of signal transduction: CaM directly intercepts incoming Ca2+ and sets the free Ca2+ level (that is, it strongly contributes to fast Ca2+ buffering) rather than responding to the lower Ca2+ level set by other buffers. This property is crucial for making CaM an efficient transducer. Our results also suggest that other Ca2+ binding proteins have a previously undescribed role in regulating the lifetime of Ca2+ bound to CaM and thereby setting the gain of signal transduction.
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Acknowledgements
We thank J. Adelman (The Vollum Institute) for purified CaM and mutants of CaM (CaMEF12 and CaMEF34), K. Baimbridge (University of Britsh Columbia) for purified calbindin and E.B.S. Faas (Syrinx Design) for help in designing the photodiode pre-amplifier. J.E.L. would like to thank W. Ross and I. Llano for conversations at the Marine Biological Laboratory Woods Hole that led to important insights into this problem. Supported by the US National Institutes of Health (NIH) grants NS027528, NS030549 and the Coelho Endowment to I.M., NIH grant DA027807 to J.E.L. and S.R., and the National Science Foundation grant NSF0642000 to S.R.
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G.C.F. was responsible for both theoretical and experimental concepts, experiments, data analysis and writing; J.E.L. and S.R. were responsible for theoretical concepts and writing; and I.M. was responsible for both theoretical and experimental concepts and writing. G.C.F., S.R., J.E.L. and I.M. together developed ideas about how the Ca2+ binding properties of multiple Ca2+ buffers could explain experimental results in dendritic spines.
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Faas, G., Raghavachari, S., Lisman, J. et al. Calmodulin as a direct detector of Ca2+ signals. Nat Neurosci 14, 301–304 (2011). https://doi.org/10.1038/nn.2746
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DOI: https://doi.org/10.1038/nn.2746
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