Ulrik Gether Lab

Ulrik Gether’s lab has long-standing expertise in studying the molecular, cellular and physiological function of monoamine receptors and transporters.

Group Leader

Professor Ulrik Gether

Department of Neuroscience
Mærsk Building, room 07-5-21

E-mail: gether@sund.ku.dk
Phone: +45 2875 7548

Research Focus

Ulrik Gether’s lab has long-standing expertise in studying the molecular, cellular and physiological function of monoamine receptors and transporters. The key goals of his lab include i) dissecting mechanisms controlling activity and availability of the monoamine (dopamine, serotonin and norepinephrine) transporters and receptors in the synapse; ii) determining how these mechanisms are affected by disease and how they are modulated by drugs; iii) investigating how genetic variation in monoamine transporters and receptors contributes to diseases characterized by altered monoamine homeostasis; and iiii) developing genetic mouse models for these diseases and decipher the underlying disease biology. Currently, the main focus of Ulrik Gether’s research is on dopamine and on diseases characterized by dysfunctional dopamine homeostasis such as parkinsonism, ADHD, and addiction. We use advanced imaging tools (e.g. super-resolution microscopy and live single molecule imaging) and biochemical approaches to study the molecular organization of the monoaminergic presynapse including the role of synaptic scaffold proteins. We use classical pharmacological tools, biophysical techniques and electrophysiology to investigate the molecular phenotype of disease-associated missense mutations in the monoamine receptors/transporters and we develop knock-in mice expressing selected disease mutations as putative novel model for dopamine pathologies. Ulrik Gether’s lab has linked missense mutations in the dopamine transporter (DAT) to early-onset parkinsonism and ADHD and it is expected that the efforts will provide important new opportunities for correlating discrete changes in dopamine homeostasis to disease characteristics. Parallel work involves use of chemogenetics and optogenetics to dissect cellular mechanisms and monoaminergic circuits responsible for the pharmacological actions of psychostimulants (e.g. cocaine and amphetamine) and ADHD medication. Our translational strategy should have a strong potential for providing a path towards new therapeutic strategies for monoaminergic diseases.

Key Publications

  • T. Rahbek-Clemmensen, M.D. Lycas, S. Erlendsson, J. Eriksen, M. Apuschkin, F. Vilhardt, T. N. Jørgensen, F. H. Hansen and U. Gether: Super-resolution microscopy reveals functional organization of dopamine transporters into cholesterol and neuronal activity-dependent nanodomains. Nature Communications (2017), 8,740.
  • S. Erlendsson, K. Gotfryd, F.H. Larsen, J.S. Mortensen, M.A. Geiger, B.J. van Rossum, H. Oschkinat, U. Gether, K. Teilum, C.J. Loland: Direct assessment of substrate binding to the Neurotransmitter:Sodium Symporter LeuT by solid state NMR. Elife (2017) Jan 24;6. pii: e19314.
  • C. Billesbølle, J. Mortensen, A. Sohail, S. Schmidt, L. Shi, H.H. Sitte, U. Gether and C.J. Loland: Transition metal ion FRET uncovers K+ regulation of a neurotransmitter:sodium symporter Nature Communications (2016) 7, 12755.
  • M. Caron and U. Gether: Structural biology: Antidepressants at work. Nature (2016) 532, 320-321.
  • A. Vuorenpää, T.N. Jørgensen, A.H. Newman, K.L. Madsen, M. Scheinin and U. Gether: Differential internalization rates and postendocytic sorting of the norepinephrine and dopamine transporters are controlled by structural elements in the N-termini. J Biol Chem (2016) 291, 5634-5651.
  • C.B. Billesbølle, M.B. Krüger, L. Shi, M. Quick, Z.Li, S. Stolzenberg, J. Kniazeff, K. Gotfryd, J. S. Mortensen, J.A. Javitch, H. Weinstein, C.J. Loland and U. Gether: Substrate-induced unlocking of the inner gate determines the catalytic efficiency of a neurotransmitter:sodium symporter. J Biol Chem (2015) 290, 26725-38.
  • F.H. Hansen, T. Skjørringe, S. Yasmeen, N.V. Arends, M.A. Sahai, K. Erreger, T. F. Andreassen, M. Holy, P.J. Hamilton, V. Neergheen, M. Karlsborg, A.H. Newman, S. Pope, S. JR. Heales, L. Friberg, I. Law, L.H. Pinborg, H.H. Sitte, C. Loland, L. Shi, H. Weinstein, A. Galli, L.E. Hjermind, L.B. Møller and U. Gether: Missense dopamine transporter mutations associate with adult parkinsonism and ADHD. J Clin Invest (2014) 124, 3107-3120.
  • L. Borre, T.F. Andreassen, L. Shi, H. Weinstei and U. Gether. The second sodium site in the dopamine transporter controls cation permeability and is regulated by chloride. J Biol Chem (2014) 289, 25764-73.
  • M. Rickhag, F. Herborg Hansen, G. Sørensen, K. Nørgaard Strandfelt, B. Andresen, K. Gotfryd, K. L. Madsen, I. Vestergaard-Klewe, I.n Ammendrup-Johnsen, J. Eriksen, A. H. Newman, E.-M. Füchtbauer, J. Gomeza, D. P. D. Woldbye, G Wörtwein and U. Gether: A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter. Nature Communications (2013) 4, 1580.
  • B. Holst, K. L. Madsen, A. M. Jansen, C. Jin, M. Rickhag, V. K. Lund, M. Jensen, V. Bhatia, G. Sørensen, A. N. Madsen, Z. Xue, S. K. Møller, D. P.D. Woldbye, K. Qvortrup, R. Huganir, D. Stamou, 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.