The European research network on signal transduction (ERNEST): toward a multidimensional holistic understanding of G protein-coupled receptor signaling

G protein-coupled receptors (GPCRs) are intensively studied due to their therapeutic potential as drug targets. Members of this large family of transmembrane receptor proteins mediate signal transduction in diverse cell types and play key roles in human physiology and health. In 2013 the research consortium GLISTEN (COST Action CM1207) was founded with the goal of harnessing the substantial growth in knowledge of GPCR structure and dynamics to push forward the development of molecular modulators of GPCR function. The success of GLISTEN, coupled with new findings and paradigm shifts in the field, led in 2019 to the creation of a related consortium called ERNEST (COST Action CA18133). ERNEST broadens focus to entire signaling cascades, based on emerging ideas of how complexity and specificity in signal transduction are not determined by receptor-ligand interactions alone. A holistic approach that unites the diverse data and perspectives of the research community into a single multidimensional map holds great promise for improved drug design and therapeutic targeting.The authors are grateful for the continued support of the European Cooperation in Science and Technology (COST) through Actions CM1207 GLISTEN and CA18133 ERNEST. On behalf of ERNEST, M.E.S. thanks the Max Delbrück Center for Molecular Medicine Berlin for support in managing the Action. M.E.S. is supported by the Deutsche Forschungsgemeinschaft (DFG) (SO1037/1-3) and the Berlin Institute of Health (Delbrück Fellowship BIH_PRO_314). J.S. acknowledges support from the Instituto de Salud Carlos III FEDER (PI18/00094) and the ERA-NET NEURON & Ministry of Economy, Industry and Competitiveness (AC18/00030). J.C. receives funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Grant Agreement No. 715052). D.E.G. is supported by the Lundbeck Foundation (R313- 2019-526) and Novo Nordisk Foundation (NNF17OC0031226). G.M.K. is funded by the National Brain Research Program (2017-1.2.1-NKP-2017-00002). M.K. acknowledges support from the Israel Science Foundation (Grants 1454/13 and 3512/19) and the DS Research Center at the University of Haifa. S.M. is supported by the Alfred Benzon Foundation (ABF-0-0-312) and Polish National Science Center (HARMONIA 2015/18/M/NZ2/00423). M.M.R. acknowledges support from the European Research Council: VIREX Grant agreement 682549, Call ERC-2105- CoG, the Independent Research Fund Denmark, the NovoNordisk Foundation (NNF17OC0029222:) and the Lundbeck Foundation (R268-2017-409). E.S. thanks the Xunta de Galicia (Centro singular de Investigacion de Galicia ́ acreditacion 2019-2022, ED431G 2019/03 and GI-1597 2017- ́ 2019 ED431B2017/70) and the European Union (European Regional Development Fund - ERDF) for financial support. J.K.S.T. acknowledges support from the DFG (HI1502/1-2) and the Novo Nordisk Foundation (Challenge Grant PRISM). N.V. is funded by grants from the Slovenian Research Agency (P3-310, J3-7605, BI-DE/18-19-015). P.K. is supported by the DFG (KO4095/4-1 and Heisenberg professorship KO4095/5- 1). All coauthors thank the stellar organizers of the eight GLISTEN meetings for their vital contributions and their associated institutes and companies for support, including the University of Warsaw (Poland), Pompeu Fabra University and Autonomous University of Barcelona (Spain), Research Centre for Natural Sciences of the Hungarian Academy of Sciences (Budapest, Hungary), Actelion Pharmaceuticals (Allschwil, Switerland), Vrije Universiteit (Amsterdam, The Netherlands), Friedrich Alexander University Erlangen and Philipps-University Marburg (Germany), University of Chemistry and Technology Prague (Czech Republic), the University of Porto (Portugal), and Sosei Heptares (Cambridge, UK). Parts of this paper are derived from the Memorandum of Understanding for the implementation of the COST Action “European Research Network on Signal Transduction” (ERNEST) CA18133