My research addresses fundamental aspects of basic pharmacology, molecular pharmacology and neuropharmacology, with certain potential translational parts. The work is divided into three Work Packages each containing a number of specific projects. Work Package 1 is focused on the pharmacology of PSD95/Disc-large/ZO-1 homology (PDZ) mediated proteins-protein interaction and how these domains might represent new attractive pharmacological targets as alternatives to surface receptors. Work Package 2 will seek to explore the controversial idea that trafficking of receptors and transporters, which in many cases is strongly integrated with their pharmacology, is determined not only by protein-protein interactions, but also by yet unappreciated protein-lipid interactions that govern localization of the receptors and transporters to areas of high membrane curvature in the plasma membrane. Work Package 3 is aimed at obtaining fundamental new understanding of dopamine signaling processes in the brain. Evidently, this has broad pharmacotherapeutic perspectives given the key role of dysfunctional dopamine signaling in many brain disease including schizophrenia, bipolar disorder, ADHD, Parkinsons’ Disease and drug abuse.
Primary research areas
- Signalling and Scaffolding Processes
- Molecular Aspects of Synaptic Plasticity
- PDZ domains
- BAR domains
- Protein Lipid Interactions
- Madsen KL and Dreyer JK. ‘High and low dopamine regulates D1 and D2 mediated signaling in striatal neurons’ Journal of Physiology, 2017 Dec 15;595(24):7271-7272
- Morten L. Karlsen*, Thor S. Thorsen*, Niklaus Johner, Ina Ammendrup-Johnsen, Simon Erlendsson, Xinsheng Tian, Jens B. Simonsen, Rasmus Høiberg-Nielsen, Nikolaj M. Christensen, George Khelashvili, Werner Streicher, Kaare Teilum, Bente Vestergaard, Harel Weinstein, Ulrik Gether, Lise Arleth** and Kenneth L. Madsen** ‘Structure of dimeric and tetrameric complexes of the BAR domain protein PICK1 determined by small-angle X-ray scattering’ Structure 2015 23 (7), 1258-1270
- Rathje M, Fang H, Bachman JL, Anggono V, Gether U, Huganir RL, Madsen KL. AMPA receptor pHluorin-GluA2 reports NMDA receptor-induced intracellular acidification in hippocampal neurons. Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14426-31.
- Holst B*, Madsen KL*, Jansen AM, Jin C, Rickhag M, Lund VK, Jensen M, Bhatia V, Sørensen G, Madsen AN, Xue Z, Møller SK, Woldbye D, Qvortrup K, Huganir R, Stamou D, Kjærulff O, Gether U. PICK1 deficiency impairs secretory vesicle biogenesis and leads to growth retardation and decreased glucose tolerance. PLoS Biol. 2013;11(4):e1001542. Epub 2013 Apr 23
- Madsen KL, Thorsen TS, Rahbek-Clemmensen T, Eriksen J, Gether U. Protein Interacting with C Kinase 1 (PICK1) Reduces Reinsertion Rates of Interaction Partners Sorted to Rab11-dependent Slow Recycling Pathway. J Biol Chem. 2012 Apr 6;287(15):12293-308.
- Madsen KL, Bhatia VK, Gether U, Stamou D BAR domains, amphipathic helices and membrane-anchored proteins use the same mechanism to sense membrane curvature., FEBS Lett. 2010 May 3;584(9):1848-55. Review.
- Thor S. Thorsen*, Kenneth L. Madsen *, Nelson Rebola, Anders Bach, Irina Moreira, Dan Peters, Tino Dyhring, Thijs Beuming, Nicolai Stuhr-Hansen, Christophe Mulle, Harel Weinstein, Kristian Strømgaard, Lars Christian B. Rønn and Ulrik Gether. Identification of a small molecule inhibitor of the PICK1 PDZ domain that inhibits synaptic plasticity. PNAS. 2010 Jan 5;107(1):413-8.
- Vikram K Bhatia, Kenneth L Madsen, Pierre-Yves Bolinger, Andreas Kunding, Per Hedegård, Ulrik Gether and Dimitrios Stamou. Amphipathic motifs in BAR domains are essential for membrane curvature sensing EMBO J. 2009 Nov 4;28(21):3303-14.
- Hatzakis NS, Bhatia VK, Larsen J, Madsen KL, Bolinger PY, Kunding AH, Castillo J, Gether U, Hedegård P, Stamou D. How curved membranes recruit amphipathic helices and protein anchoring motifs. Nat Chem Biol. 2009 Nov;5(11):835-41.
- Madsen KL, Beuming T, Niv MY, Chang CW, Dev KK, Weinstein H, Gether U. Molecular determinants for the complex binding specificity of the PDZ domain in PICK1. J Biol Chem. 2005 May 27;280(21):20539-48.
Kenneth Madsen, Thor Seneca Thorsen, Dan Peters, Tino Dyhring, Lars Christian Rønn, Ulrik Gether. PDZ DOMAIN MODULATORS. Danish patent application No. PA 2007 00828
(filed on 8 June 2007) and US provisional application No. 60/942,860 was filed on 3 June 2008
(Application No. PCT/EP2008/056814)