Increased levels of the second messenger lipid diacylglycerol (DAG) induce downstream signaling events including the translocation of C1-domain-containing proteins toward the plasma membrane. Here, we introduce three light-sensitive DAGs, termed PhoDAGs, which feature a photoswitchable acyl chain. The PhoDAGs are inactive in the dark and promote the translocation of proteins that feature C1 domains toward the plasma membrane upon a flash of UV-A light. This effect is quickly reversed after the termination of photostimulation or by irradiation with blue light, permitting the generation of oscillation patterns. Both protein kinase C and Munc13 can thus be put under optical control. PhoDAGs control vesicle release in excitable cells, such as mouse pancreatic islets and hippocampal neurons, and modulate synaptic transmission in Caenorhabditis elegans. As such, the PhoDAGs afford an unprecedented degree of spatiotemporal control and are broadly applicable tools to study DAG signaling.
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We thank M. Sumser, J. Broichhagen and T. Fehrentz for insightful discussions leading to the preparation of the manuscript, and M. Duca, S. Wouters, R. Mitchell and N. Johnston for experimental assistance. We thank F. Stein for providing macros for image analysis. We are grateful for the technical support of EMBL's Advanced Light Microscopy Facility. D.T. and J.A.F. are supported by the Deutsche Forschungsgemeinschaft (DFG) (SFB 1032 project B09, TRR 152) and the European Research Council (ERC Advanced Grant 268795 to D.T.). C.S. is supported by the DFG (TRR 83 and TRR 186). D.A.Y. was funded by the EIPOD Programme at EMBL, EU grant 229597 and an IOCB installation grant. D.J.H. was supported by Diabetes UK RD Lawrence (12/0004431), EFSD/Novo Nordisk Rising Star and Birmingham fellowships. D.J.H. and G.A.R. were supported by MRC project (MR/N00275X/1) and Imperial Confidence in Concept (ICiC) grants. G.A.R. was supported by Wellcome Trust Senior Investigator (WT098424AIA) and Royal Society Wolfson Research Merit awards and grants from the UK Medical Research Council (MR/J0003042/1, MR/L020149/1 and MR/L02036X/1), the Biological and Biotechnology Research Council (BB/J015873/1) and Diabetes UK (11/0004210; 15/0005275). J.N. was supported by DFG grants FOR1279 GO1011/4-1 and GO1011/4-2 and Cluster of Excellence Frankfurt (EXC115) (all grants to A.G.).
The authors declare no competing financial interests.
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Frank, J., Yushchenko, D., Hodson, D. et al. Photoswitchable diacylglycerols enable optical control of protein kinase C. Nat Chem Biol 12, 755–762 (2016). https://doi.org/10.1038/nchembio.2141
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