EU Project

Communication between cells occurs through signaling molecules like hormones or neurotransmitters that are recognized by specific receptors, which constitute the primary class of drug targets. We investigate their function and regulation in various model systems to explore general mechanisms and functional principles. Over the last few years, we have developed a variety of techniques to visualize receptor activation, inactivation and the resulting signals by means of new sensors and fluorescence microscopy methods. This allows us to directly observe receptors and signaling mechanisms „at work“. This approach enables us to analyze the speed and localization of signals and receptor even at the level of single molecules in isolated cells and in vivo.

Recently we were able to demonstrate the similarity of the molecular activation mechanisms between class A GPCRs and Frizzled receptors and also provided evidence for G-protein coupling of Frizzled 5 receptors.

Furthermore, together with pharmaceutical chemists at the University of Wuerzburg (Prof. Dr. Ulrike Holzgrabe and Prof. Dr. Michael Decker), we were able to describe the first M1 selective muscarinic receptor ligand that can be isomerized by light between an agonist or antagonist. Such ligands are called photoswithcable ligands and offer a new way to control receptor activity by light and open a new area of photopharmacology.

Funding:

EU-Förderung Grant agreement number 608180: Marie-Curie International Training Network: „WntsApp WNT-mediated signal relay in stem cells and oncogenesis from basic biology to applications“ ; Funding period: 2013-2017

Förderung durch das „Bayrisches Staatsministerium für Bildung und Kultus, Wissenschaft und Kunst“: Elitenetzwerk Bayern Internationale Doktorandenkolleg „Receptor Dynamics: Emerging Paradigms for Novel Drugs“; Teilprojekt 6, Funding period: 2014-2018

References:

1. Messerer, M. Kauk, D. Volpato, M.C. Alonso Canizal, J. Klöckner, U. Zabel, S. Nuber, C. Hoffmann*, U. Holzgrabe (2017)
   FRET Studies of Quinolone-Based Bitopic Ligands and their structural analogues at the Muscarinic M1 Receptor.
   ACS Chem Biol. 12, 833-843; doi: 10.1021/acschembio.6b00828.
    *Co-Corresponding author
   
   
2. Agnetta, M. Kauk, M.C. Alonso Canizal, R. Messerer, U. Holzgrabe, C. Hoffmann*, M. Decker (2017)
   A photoswitchable dualsteric ligand controlling receptor afficacy.
   Angewandte Chemie International Edition 56 (25): 7282-7287; doi: 10.1002/anie-201701524
   *Co-Corresponding author
   
   
3. Schreiber, M. Kauk, H. Heil, M. Emmerling, I. Tesmer, M. Kamp, S. Höfling, U. Holzgrabe, C. Hoffmann, K. Heinze (2018)
   Enhanced fluorescence resonance energy transfer in G-protein-coupled receptor probes by nano-coated microscopy coverslips.
   ACS Photonics, 5(6): 2225-2233; doi: 10.1021/acsphotonics.8b00072
   
   
4. Littmann, T. Ozawa, C. Hoffmann, A. Buschauer and G. Bernhardt (2018)
   A split luciferase-based probe for quantitative proximal determination of Gαq signalling in live cells
   Scientific Reports, 8:17179; doi: 10.1038/s41598-018-35615-w
   
   
5. S.C. Wright, M.C. Alonso Cañizal, T. Benkel, K. Simon, C. Le Gouill, P. Matricon, Y. Namkung, V. Lukasheva, G.M. König, S.A. Laporte, J. Carlsson, E. Kostenis, M. Bouvier, G. Schulte, C. Hoffmann (2018)
   FZD5 is a Gq-coupled receptor exhibiting the functional hallmarks of prototypical GPCRs.
   Science Signaling, 11, issue 559, eaar5536; doi: 10.1126/scisignal.aar5536