Claus Juul Løland – University of Copenhagen

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Center for Synthetic Biology > Meet the Researchers > Claus Juul Løland

Claus Juul Løland

Associate Professor

Claus Juul Løland
Molecular Neuropharmacology Group
Department of Neuroscience and Pharmacology
Faculty of Health Sciences
cllo@sund.ku.dk





Our research is focused on molecular pharmacology and structures of neurotransmitter transporters. We examine the function of neurotransmitter transporters in order to highlight the effects of drugs such as cocaine as well as antidepressive medication. One potential outcome of our work is the development of next generation of antidepressive medication with an improved clinical profile. The new drugs will be better at fine-tuning the activity of SERT, a transporter controlling the removal of serotonin from the brain.

Research
Each kind of neurotransmitter in the brain has its own transporter and by changing their activities it is possible to change the intercellular communication between nerve cells, which also means that the personality is changed. This is how antidepressants and cocaine exert their function. By obtaining more knowledge about the molecular function of these neurotransmitter transporters, we will get closer to a basic understanding of how these transporters can remove neurotransmitters and how this process can be blocked by e.g. cocaine.  

A central cause to the development of depression is too low levels of the neurotransmitter serotonin. Therefore, traditional antidepressants function by completely blocking the serotonin transporter (SERT), which removes serotonin from the brain. However, new research from our group seems to reveal that SERT has additional functions than initially thought. This opens for new possibilities affect the activity of this transporter. The goal is to develop new medication which modulates the activity of SERT instead of a complete blockage as the current antidepressants do.

  

Figure: The binding of cocaine to the dopamine transporter. A molecular model of how a high-affinity cocaine analogue (green) binds to its binding site in the dopamine transporter (helices in shades of blue). The interacting residues are shown in yellow with central interactions depicted (dotted lines 4, 5 and 6). Spheres are possible binding sites for sodium (red) and chloride (orange). Only transmembrane domain (TM) 1, 3, 6 and 8 are shown, the remaining protein has been removed for clarity (picture taken from Beuming et al., (2008) Nature Neuroscience).

 

CV

2009-present Associate Professor, Faculty of Health and Medical Sciences, University of Copenhagen.
2000-2003 PhD, Faculty of Health and Medical Sciences, University of Copenhagen
1996-1999 MSc in Human Biology, Faculty of Health and Medical Sciences, University of Copenhagen.
1992-1996 BSc in Molecular Biology, Roskilde University.

 
Collaboration partners from UNIK
Søren Rasmussen
Tom Vosch
Lise Arleth
Dimitros Stamous
Karen Martinez
Marite Cardenas
Ulrik Gether

Selected Scientific Publications

Jagalski, V., Barker, R., Thygesen, M.B., Gotfryd, K., Kruger, M., Shi, L., Maric, S., Bovet, N., Moulin, M., Haertlein, M., Gunther Pomorski, T., Loland, C.J. and Cardenas, M.  Grafted Biomembranes Containing Membrane Proteins - The Case for the Leucine Transporter. Soft Matter 11, 7707-7711 doi: 10.1039/C5SM01490E (2015) I.F. 4,457

Billesbølle, C.B., Krüger, M.B., Shi, L., Quick, M., Li, Z., Stolzenberg, S., Kniazeff, J., Gotfryd, K., Mortensen, J.S., Javitch, J.A., Weinstein, H.,  Loland, C.J . and Gether, U. Substrate-induced unlocking of the inner gate determines the catalytic efficiency of a neurotransmitter:sodium symporter. Journal  of Biological Chemistry doi: 10.1074/jbc.M115.677658 (2015) I.F. 5,328

Hansen, F. H., Skjorringe, T., Yasmeen, S., Arends, N.V., Sahai, M.A., Erreger, K., Andreassen, T.F., Holy, M., Hamilton, P.J., Neergheen, V., Karlsborg, M., Newman, A.H., Pope, S., Heales, S.J.R., Friberg, L., Law, I., Pinborg, L.H., Sitte, H.H., Løland, C., Shi, L., Weinstein, H., Galli, A., Hjermind, L.E., Møller, L.B., Gether, U.  Missense dopamine transporter mutations associate with adult parkinsonism and ADHD.   Journal of Clinical Investigation 124, 3107 3120,  doi:10.1172/jci73778 (2014)

Okunola-Bakare, O. M., Cao, J., Kopajtic, T., Katz, J.L., Løland, C.J., Shi, L., and Newman, A.H. Elucidation of Structural Elements for Selectivity across Monoamine Transporters: Novel 2- (Diphenylmethyl)sulfinyl acetamide (Modafinil) Analogues. Journal of Medicinal Chemistry 57, 1000-1013,  doi:10.1021/jm401754x (2014)


Løland, C. J.The use of LeuT as a model in elucidating binding sites for substrates and inhibitors in neurotransmitter transporters. Biochimica et Biophysica Acta doi:10.1016/j.bbagen.2014.04.011, epub ahead of print (2014).

Chae, P. S., Rana, R.R., Gotfryd, K., Rasmussen, S.G.F., Kruse, A.C., Cho, K.H., Capaldi, S., Carlsson, E., Kobilka, B., Løland, C.J., Gether, U., Banerjee, S., Byrne, B., Lee, J. K., Gellman, S. H. Glucose-Neopentyl Glycol (GNG) amphiphiles for membrane protein study. Chemical Communications 49, 2287-2289, doi:10.1039/c2cc36844g(2013).

Løland, C. J., Mereu, M., Okunola, O.M., Cao, J., Prisinzano, T.E., Mazier, S., Kopajtic, T., Shi, L., Katz, J.L., Tanda, G., Newman, A.H. R-Modafinil (Armodafinil): A Unique Dopamine Uptake Inhibitor and Potential Medication for Psychostimulant Abuse. Biological Psychiatry 72, 405-413, doi:10.1016/j.biopsych.2012.03.022 (2012).

Chae, P. S., Rasmussen, S.G.F., Rana, R.R., Gotfryd, K., Kruse, A.C., Manglik, A., Cho, K.H., Nurva, S., Gether, U., Guan, L., Løland, C. J., Byrne, B., Kobilka, B. K., Gellman, S. H. A New Class of Amphiphiles Bearing Rigid Hydrophobic Groups for Solubilization and Stabilization of Membrane Proteins. Chemistry-a European Journal 18, 9485-9490, doi:10.1002/chem.201200069 (2012).

Plenge, P., Shi, L., Beuming, T., Te, J., Newman, A.H., Weinstein, H., Gether, U., and Løland, C.J. Steric Hindrance Mutagenesis in the Conserved Extracellular Vestibule Impedes Allosteric Binding of Antidepressants to the Serotonin Transporter. Journal of Biological Chemistry 287, doi:10.1074/jbc.M112.371765 (2012).

Chae, P. S., Rasmussen, S.G.F., Rana, R.R., Gotfryd, K., Chandra, R., Goren, M.A., Kruse, A.C., Nurva, S., Løland, C.J., Pierre, Y., Drew, D., Popot, J.-L., Picot,D., Fox,B. G., Guan,L., Gether,U., Byrne,B., Kobilka, B., Gellman, S. H. Maltose-neopentyl glycol (MNG) amphiphiles for solubilization, stabilization and crystallization of membrane proteins. Nature Methods 7, 1003-U1090, doi:10.1038/nmeth.1526 (2010).

Chae, P. S., Gotfryd, K., Pacyna, J., Miercke, L.J.W., Rasmussen, S.G.F., Robbins, R.A., Rana, R.R., Løland, C.J., Kobilka, B., Stroud, R., Byrne, B., Gether, U., Gellman, S.H. Tandem Facial Amphiphiles for Membrane Protein Stabilization. Journal of the American Chemical Society 132, 16750-16752, doi:10.1021/ja1072959 (2010).

Beuming, T. , Kniazeff, J., Bergmann, M.L., Shi, L., Gracia, L., Raniszewska, K., Newman, A.H., Javitch, J.A., Weinstein, H., Gether, U., Løland, C.J. The binding sites for cocaine and dopamine in the dopamine transporter overlap. Nature Neuroscience 11(7), 780-789. doi:10.1038/nn.2146 (2008).

Løland, C.J. , Desai, R.I., Zou, M.-F., Cao, J., Grundt, P., Gerstbrein, K., Sitte, H.H., Newman, A.H., Katz, J.L., Gether, U. Relationship between conformational changes in the dopamine transporter and cocaine-like subjective effects of uptake inhibitors. Molecular Pharmacology 73(3): 813-823, doi: 10.1124/mol.107.039800 (2007).

Kniazeff, J., Løland, C.J., Goldberg, N., Quick, M., Das, S.K., Sitte, H.H., Javitch, J.A., Gether, U. Intramolecular cross-linking in a bacterial homolog of mammalian SLC6 neurotransmitter transporters suggests an evolutionary conserved role of transmembrane segments 7 and 8. Neuropharmacology 49(6), 715-723 (2005).

Granas, C., Ferrer, J., Løland, C.J. , Javitch, J.A., Gether, U.N-terminal truncation of the dopamine transporter abolishes phorbol ester- and substance P receptor-stimulated phosphorylation without impairing transporter interanalization. Journal of Biological Chemistry 278 (7), 4990-5000 (2003).