Madsen Lab – University of Copenhagen

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CNS > Research > Section for Molecular and Cellular Neuroscience > Madsen Lab

Madsen Lab

My lab has long-standing expertise in studying the molecular and cell biological function of synaptic scaffold proteins as well as trafficking of neurotransmitter receptors and transporters.

The key goals of the lab include:

i) dissecting molecular mechanisms of protein-protein and protein-membrane interactions of scaffold proteins involved in synaptic plasticity including de novo reconstruction of synaptic structures using supported cell membrane sheets;

ii) understanding neuronal signaling and trafficking mechanisms in synaptic plasticity including coupling between Ca2+ and pH changes, general changes of recycling and heterogenous D1 receptor signaling;

iii) development of small molecule and peptidergic inhibitors of scaffold proteins central in synaptic plasticity and important for development of neuropathic pain, drug addiction and neurodegenerative diseases; and

iiii) unraveling the widespread role of protein-membrane based trafficking motifs in GPCRs, vesicular and plasma membrane neurotransmitter transporters as well as receptors for viral and αsynuclein cell entry.

We use advanced imaging tools (e.g. super-resolution microscopy and total internal reflection microscopy of pH sensitive fluorophores) as well as in vitro/ex vivo biochemical approaches to study the molecular processes governing synaptic plasticity. We use classical imaging based method to study protein trafficking coupled with flow cytometry for high throughput multicomponent analysis. Moreover we have strong biochemical and biophysical expertise for studying protein structure function relations on purified proteins and in particular we have focused on protein and peptide interactions with lipid membranes.

Combining these approaches, we aim to understand fundamental cell biological processes in neurons and synaptic transmission, which will enable identification of novel disease targets and development of alternative treatment strategies and therapeutics.

Key publications last 10 years

  • Karlsen ML*, Thorsen TS*, … Gether U, Arleth L and Madsen KL ‘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
  • B. Holst*, K. L. Madsen*, A. M. Jansen, … O. Kjærulff and U. Gether: PICK1-Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance. PLOS Biology  (2013) 11:e1001542
  • Rickhag M, Hansen FH, Sørensen G, Strandfelt KN, Andresen B, Gotfryd K, Madsen KL, Vestergaard-Klewe I, Ammendrup-Johnsen I, Eriksen J, Newman AH, Füchtbauer EM, Gomeza J, Woldbye DP, Wörtwein G, Gether U.: A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopaminę transporter. Nature Communications (2013) 4, 1580
  • 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.
  • T. S. Thorsen*, K. L. Madsen*, … K. Strømgaard, L. C. Rønn and U. Gether: Identification of a small molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc Natl Acad Sci U S A  (2010) 107, 413-418
  • 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

Overall publication metrics: Number of peer reviewed papers: 30; H-index: 14; i10-index: 17